Health Professional News

Crack the Case: Hepatitis cases linked to adenovirus infection still a mystery

A mysterious wave of acute hepatitis in children remains under investigation and now spans 46 states and at least 11 countries in Europe and the Americas. In a March 2023 report, the Centers for Disease Control and Prevention (CDC) indicated 390 kids in the U.S. are under investigation for acute cases of hepatitis with possible links to contributing factors including adenovirus, coinfections, environmental exposures and medications; more than 50 kids had a confirmed adenovirus infection. The CDC is tracking the 390 cases retrospectively since October 2021. These cases are unique in that typical causes for liver injury such as viral hepatitis A-E have not been found. Worldwide, most children have fully recovered, although about 10 percent needed liver transplants and the vast majority (90 percent) have been hospitalized.  

In September 2022, an episode of Talking Pediatrics, “Crack the Case: Hepatitis, Adenovirus and a Boy with Yellow Eyes,” explored the case of a 4-year-old boy who presented at Children’s Minnesota with symptoms of possible hepatitis. Dr. Bryan Fate, primary care physician, and Dr. Rashedat Oshodi, resident from the University of Minnesota, discussed the case and the medical decisions that were involved. Crack the Case is a special series of podcasts where guest hosts dive into real cases from our Minneapolis clinic to highlight medical decision-making and approaches to general pediatrics topics. 

The clinical assessment 

In this case, a four-year-old Hispanic boy presented to the clinic with complaints of a rash and yellowing of the eyes. Parents reported that two weeks prior he had had non-bloody, non-bilious vomiting and stomach pain, which lasted for a week and then resolved. His appetite was low; he only wanted to drink fluids and eat small bites of food. His older siblings also had the same symptoms that resolved after a week.  

The boy’s physical exam at the clinic revealed no fever, a normal heart rate and blood pressure, and he was playful and interactive. He had markedly yellow sclera. His liver was slightly enlarged but not tender. The boy had no splenic enlargement, dilated abdominal veins, or any signs of liver disease. He had a facial rash with very fine papules, bilaterally left and right and over the bridge of his nose. His parents said the rash appeared the day before they came to the clinic, and it started at the tip of his nose before extending bilaterally to both cheeks. 

The boy had no stool changes, diarrhea, constipation, melena or hematochezia (blood in stool). He also did not have painful urination and there was no penile swelling noted. There was no recent travel or animal exposures, and he was not on any medications prior to the onset of any symptoms, including Tylenol. There was no family history of gastrointestinal (GI) disease, hemolytic blood diseases, or any liver failure. 

The parents reported the boy has historically been a healthy kid. There was no history of hospitalizations or surgeries. His vaccinations were all current, including hepatitis B. 

Diagnostic considerations 

Hepatitis is inflammation of the liver that can be caused by infections, toxins (such as alcohol), drugs, or certain medical conditions. Infectious hepatitis is the most common type in kids. The doctors ruled out the following causes for the boy’s illness: 

  • Obstructive/mechanical cholestasis (reduced or stopped bile flow), which causes jaundice, dark urine, light-colored stool. The patient had yellowing in eyes but did not have light-colored stool. His liver ultrasound did not demonstrate stones or mass with normal alpha fetoprotein as in hepatic malignancy.
  • Typical infectious causes (Hepatitis A-C), CMV, EBV. There was no family history or neonatal exposure, and the boy is adequately vaccinated for hepatitis B. Negative serologies. 
  • Ingestion of medications or exposure to toxins (i.e., Tylenol, chemicals, nutritional supplements). No concern about ingestion or exposure.
  • Autoimmune hepatitis with reassuring A1AT, IgG, ANA, anti-LKM, anti-smooth muscle antibody. 
  • Vascular obstruction such as right-sided heart failure or Budd Chiari. Liver ultrasound with doppler was performed and no evidence of ascites.  
  • Gianotti-Crosti Syndrome, which is usually a delayed immune reaction to a viral illness like respiratory infections or hepatitis B. It typically begins in other places like buttocks and spreads. The boy only had a rash on his face. 
  • Hemolytic anemia (red blood cells are destroyed faster than they’re made), which causes paleness, yellowish skin and eyes, dark urine. The complete blood count (CBC) ruled out hemolytic anemia. Read the lab test and imaging results here. 

Synthetic liver considerations

  • Coagulation studies were abnormal prompting hospitalization. 
  • Total protein and albumin were normal without edema. 
  • No evidence of encephalopathy such as confusion or lethargy with normal ammonia. 

Ultimately, the four-year-old was hospitalized and the clinical team also ruled out genetic diseases including celiac disease (gluten reaction), Wilson’s disease (copper accumulates in liver, brain) and cystic fibrosis (damages lungs and digestive tract). The boy was positive for norovirus (not adenovirus). 

The young patient was discharged after two days in the hospital and followed closely in the GI clinic and primary care clinic for the next four weeks. Over time his liver enzymes and coagulation studies normalized, and his appetite returned. He made a full recovery. 

Refresher: norovirus vs. adenovirus

Norovirus is a very contagious virus that causes vomiting, diarrhea, nausea and stomach pain. Adenoviruses most commonly cause respiratory illness, ranging from the common cold to pneumonia, croup and bronchitis. Depending on the type, adenoviruses can cause other illnesses such as gastroenteritis, conjunctivitis, cystitis, and, less commonly, neurological disease. 


Dr. Fate summarized the findings saying, “Infection is the number one cause of acute hepatitis in children. Adenovirus was not found [in this patient], but we’ve seen this kind of sweeping wave of [hepatitis] cases associated with it, and he did test positive for norovirus.” 

Dr. Oshodi added, “Hepatitis has many causes, and management has to be different depending on the specific diagnosis. As clinicians, we need to be aware of that and perform an organized search to make sure we identify the responsible disease – in our case, a [presumed] case of a viral hepatitis due to norovirus – then initiate the appropriate treatment. Given that we’ve seen this wave of hepatitis associated cases with adenovirus, this has to be a consideration.” 

Bottom line: There’s a lot that still needs to be learned about a hepatitis-adenovirus association. The American Academy of Pediatrics’ Red Book continues to recommend adenovirus testing in children with acute hepatitis of unknown etiology and reporting all cases to state public health authorities and the Centers for Disease Control and Prevention (CDC). 

Listen to the podcast or read the transcripts here 

Mai Songsawatwong