Liver abnormalities in severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, including hepatitis and cholestasis, have been observed in adults and is associated with worse outcomes. We describe two adolescents with cholestasis and hepatitis with mild presentation of SARS-CoV-2 lacking typical symptoms. Our intention is to raise index of suspicion for testing and protective equipment use.
) SARS-CoV-2 affects adults and children in dramatically different ways. Early pediatric epidemiologic data of 3 studies with 1,391(5) and 2,135(6) children from Wuhan, China and 2,572(4) US children demonstrated that the majority had mild symptoms compared with adults, but may serve as vectors of transmission in society.(
) North American Pediatric Intensive Care Units (PICU) collaborative report from March-April 2020 confirmed these findings but also noted that severe illness in children is significant, however far less frequent, compared with adults.(
) Infants and children with co-morbidities were particularly vulnerable to COVID-19(6, 7).
) Liver abnormalities described included elevation of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), mildly elevated bilirubin levels, high gamma-glutamyl transferase (GGT) and low albumin levels (2.6-3.3 g/L)(
We present two cases of acute hepatitis with clinically apparent jaundice and cholestasis without biliary obstruction associated with SARS-CoV-2 infection. Both adolescents lacked other typical features of COVID-19 respiratory tract infection and had a mild disease course. Given significant variability of COVID-19 symptoms in children, providers had high index of suspicion and tested these patients with unusual presentation.
Institutional Review Board (IRB) approval was obtained at Albert Einstein College of Medicine. These case reports were exempt from IRB at Feinstein Institutes for Medical Research of Northwell Health. Patients described here are unique to this report and will be excluded from our registry of COVID-19 patients. Demographic information, clinical, laboratory and imaging results were examined.
A 16-year-old boy presented to the emergency department (ED) of the Children’s Hospital at Montefiore in the Bronx, New York with one day of scleral icterus, epigastric abdominal pain, nausea, two episodes of non-bloody, non-bilious emesis, decreased oral intake, and dark urine. No respiratory symptoms or diarrhea were present. Patient and family reported staying at home in the preceding three weeks without any exposure to sick contacts, a known COVID-19 case, essential workers, or travel. Patient denied any drug or alcohol use.
Table 1Patient’s Characteristics
Given his prior history of cholelithiasis with cholecystectomy and concern for an obstructive process, magnetic resonance cholangiopancreatography (MRCP) was obtained to further assess for any anatomic abnormalities and revealed no evidence of intra- or extrahepatic ductal dilatation or biliary stricture. Although he had no fever or respiratory symptoms, COVID-19 hepatitis was considered in the differential diagnosis, and his SARS-CoV-2 polymerase chain reaction (PCR) test was positive.
The patient was admitted for monitoring. No treatment targeting COVID-19 was initiated due to lack of supporting evidence and otherwise wellbeing. Airborne/special contact precautions were maintained during his hospitalization. The patient never developed respiratory or other systemic inflammatory symptoms. After 24 hours his direct bilirubin level fell to 0.4 mg/dL. Three weeks after discharge, AST/ALT decreased to 47/76 U/L and total bilirubin remained elevated at 1.7 mg/dL with normal direct fraction < 0.5 mg/dL (consistent with prior diagnosis of Gilbert).
Case t 2.
A 17-year-old previously healthy young woman presented to the ED at Cohen Children’s Medical Center in New York’s Nassau County with four days of fever, acute onset of jaundice, and dark urine. She had developed urinary urgency without fever or dysuria six days prior to presentation. She was seen at a clinic where urine culture was obtained that was negative. Four days prior to presentation her urine turned dark orange/brown and she developed fevers with maximum temperature of 103F. She also complained of chills, night sweats and had an episode of non-bloody diarrhea. On the day of presentation, she noted that the whites of her eyes appeared yellow. No respiratory symptoms (cough, congestion and/or difficulty breathing) were present. She had no abdominal pain, nausea, or vomiting. She no longer experienced urinary urgency or dysuria. There was no prior history of cholestasis, jaundice, or liver disease. She denied any drug or alcohol use. She confirmed no exposure to a case of COVID-19 or recent travel.
In the ED, she had tachycardia to 111 bpm and was afebrile. Physical examination revealed a non-obese female with scleral icterus without abdominal tenderness. Laboratory test results revealed elevation of serum AST and ALT to 154 and 294 U/L, respectively. One month prior, AST and ALT levels obtained during annual physical examination were normal (11 and 15 U/L, respectively). Total and direct bilirubin levels were 3.4/1 mg/dL and GGT was 147 U/L. Liver synthetic function, INR, albumin, and platelets were normal (Table).
An abdominal US revealed hepatomegaly (16.1 cm span) with normal echogenicity and without any gallstones, sludging or bile duct dilation. SARS-CoV-2 PCR test on nasal specimen was positive. She was discharged home from the ED with close follow up. Two weeks later serum AST and ALT levels were 56 and 147 U/L respectively, with total and direct bilirubin levels of 0.6/0.2 mg/dL.
) A 55-day old infant with pneumonia and acute cardiac injury developed mild hepatitis (AST/ALT of 100/84 IU/L) and conjugated hyperbilirubinemia (TB/DB 2/1.4 mg/dL) which resolved with clinical improvement.(
) One study of adults with severe COVID-19 admitted to the intensive care unit (ICU), did not report a significant difference in percentage of patients with liver dysfunction between survivors and non-survivors, although biochemical test results of the non-survivors’ were more abnormal.(
), hepatic congestion associated with high positive end expiratory pressure and/or direct liver damage by virus-induced T lymphocytes.(
) High levels of pro-inflammatory cytokine molecules were found in patients with COVID-19 activating T-helper-1 (Th1) cell response and inducing dysregulation of the innate immune response.(
) Postmortem liver biopsy obtained in a patient with COVID-19 from Wuhan, China demonstrated moderate micro-vesicular steatosis and mild lobular and portal activity indicating either virus- or drug-induced liver injury.(
) Chai et al was able to identify expression of ACE 2 within bile duct epithelial cells (cholangiocytes) but not hepatocytes in healthy liver tissues.(
) Cholangiocytes are known to play an important role in liver regeneration and immune response(20), which could be a mechanism underpinning acute cholestasis we observed.
) as well as any signs of inflammatory dysregulation seen in MIS-C.(
) Both patients were non-obese adolescents without underlying liver disease or other co-morbidities.
Our patients had a mild clinical course. Extensive evaluation for cholestasis may not be necessary in otherwise healthy pediatric patients with SARS-CoV-2 infection. Imaging can be limited to those with symptoms concerning for biliary obstruction. Further studies are needed to ascertain whether a higher rate of cholestasis is associated with SARS-CoV-2 infection in children and adolescents. Recognition and identification of children and adolescents with acute cholestasis secondary to SARS-CoV-2 is important for management, appropriate infection control and proper use of personal protective equipment.
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The authors declare no conflict of interest.
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