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Clinical Infection & Immunity

Case Report

Volume 5, Number 1, March 2020, pages 4-6

Cholestatic Hepatitis Induced by Epstein-Barr Virus in Childhood

Primary Epstein-Barr virus (EBV) infection may result in acute hepatitis, which usually manifests with slightly elevated transaminase levels and very rarely jaundice [1, 2]. The pathogenetic mechanism that causes the breakdown of liver cells and provokes cholestasis during the infection is not fully investigated. It is believed that EBV has no direct cytopathic effect on the cells, but its breakdown is due to the toxic action of free radicals. Patients with EBV infection have autoantibodies against superoxide dismutase (an antioxidant enzyme) [3, 4]. Although biochemical evidence of hepatic impairment is common in older children with EBV infectious, the signs and symptoms associated with impaired biliary flow such as jaundice and itching are rare; they occur in about 5-7% of all cases [5]. We present a clinical case of a 5-year-old boy with EBV-induced hepatitis presenting with cholestasis and prolonged duration.

A previously healthy child was admitted with fever, rash, swollen cervical lymph node and fatigue. He was treated symptomatically with antipyretics for 3 days. In the morning of the third day, his mother noticed the darkening of his urine. After examination by a doctor, the patient was hospitalized in our clinic with a diagnosis of acute viral hepatitis of unspecified etiology.

The examination revealed small macular rash on the patient’s chest, abdomen and back. The sclerae were icteric. The throat was sore with hypertrophic tonsils; “raspberry tongue” was present. The abdomen was soft, the liver was palpable in the size of 2.5 cm under the costal margin, and the spleen is enlarged by about 1 cm. An enlarged cervical lymph node was found, about 4 cm in diameter, soft and elastic, not painful.

The initial laboratorial evaluation showed a complete blood count with 13,000 leucocytes/µL, 35.4% lymphocytes, 19.0% atypical lymphocytes, elevated enzymes: aspartate aminotransferase (AST) 228 IU/L (normal value to 44 IU/L), alanine aminotransferase (ALT) 411 IU/L (normal value to 44 IU/L), γ-glutamyl transpeptidase (γ-GT) 192 IU/L (normal value to 30 IU/L), alkaline phosphatase (ALP) 1,035 IU/L ((normal value to 425 IU/L, hyperbilirubinemia (total bilirubin 14.83 mg/dL, direct bilirubin 11.39 mg/dL), bilirubinuria and hypoalbuminemia (minimum 2.4 g/dL) (Table 1). The prothrombin time and the C-reactive protein were normal.

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Table 1. Laboratory Tests by Dates

No pathogenic bacteria were isolated in the microbiological test of throat. Of the serological tests, only the anti viral capsid antigen (VCA)-EBV-IgM was positive; the tests for IgG antibodies against EBV and the other hepatotropic viruses (A, B, C, D, E) and cytomegalovirus (CMV), parvovirus B19 and herpes simplex 1, were negative.

The sonography of the abdominal organs showed homogeneous hypoechogenicity which is the evidence of diffuse inflammation of the liver, moderate hepatomegaly and splenomegaly. The gallbladder was enlarged, no wall thickening, no signs of inflammation or lithiasis. The pancreas looked normal.

The child had a test result confirming the hypothesis of acute EBV infection. All other causative agents of acute viral hepatitis were excluded. A pediatric hematologist was consulted due to the enlarged lymph node and the persistent fever; and the suspicion of onco-hematological disease was rejected. A pediatric rheumatologist was also consulted and Kawasaki disease was rejected as a possible cause of the disease.

The child was hospitalized in the clinic for 17 days. At the onset of the disease (the first 3 or 4 days), toxic-infectious, rash, lymphonodular, icteric and hepatosplenomegalic syndromes were present. Subsequently, a severe astheno-adynamic syndrome developed and the icterus intensified. Persistent itching appeared. The levels of bilirubin, γ-GT and ALP increased drastically. The fever persisted until the 14th day, when gross lamellar peeling started. A treatment with infusion of glucose solutions, ceftriaxone 2 × 50 mg/kg, sylimarin, transmetil and methylprednisolone was performed. The child was released from the clinic after a 17-day inpatient treatment in an improved overall condition, with reduced hepatosplenomegaly and lymphadenomegaly, and with decreased transaminase and cholestatic enzyme levels. After a 2-month course of treatment with a hepatoprotective drug and an immunostimulator at the patient’s home, the patient’s transaminase, bilirubin and cholestatic enzyme levels were normalized.

The Ethics Committee of the University Hospital for Infectious and Parasitic Diseases “Prof. Iv. Kirov” (no. 21, November 11, 2018) approved the case report.

Based on the clinical and laboratory evidence, we diagnosed acute EBV-induced hepatitis with cholestasis in this case. Given the prolonged course of the infection and the unusual occurrence of jaundice, we also tested for all other causative agents of viral hepatitis. The abdominal sonography showed no evidence of extrahepatic cholestasis. EBV is a very common infectious agent during childhood, affecting 345 - 671/100,000 persons aged 15 - 19 years, with decreasing incidence in older age groups (2 - 4/100,000 in the population aged over 34 years) [2, 4]. It is usually associated with mild and self-limiting hepatitis, but a 55% incidence of severe cholestatic hepatitis has been reported in adults. EBV infection should be considered when elevated transaminase levels and a self-limiting cholestatic pattern are present even when other typical symptoms are lacking [6, 7].

Jaundice during EBV infections can be caused by autoimmune hemolytic anemia or cholestasis (due to acalculous cholecystitis, obstruction of the bile duct due to abdominal lymphadenopathy and cholestatic hepatitis) [1, 7, 8]. Jaundice is more common in people over 35 years (30%) than in people aged less than 35 years (3%) [4, 5].

Increased bilirubin levels have been reported in up to 35% of patients with infectious mononucleosis, but rarely described without accompanying splenomegaly, rash or tonsillitis [3, 9].

Our patient had hepatitis with marked cholestasis, with increased direct bilirubin and cholestatic enzymes, and his main clinical symptom was jaundice accompanied by intense itching. The abdominal sonography showed lack of cholecystitis or biliary obstruction. The serological tests only proved an acute EBV infection.

With this study, we emphasize the need to consider the EBV infection in the differential diagnosis of cholestatic hepatitis in childhood.

Acknowledgments

We thank the parents for allowing us to describe this case.

Financial Disclosure

None to declare.

Conflict of Interest

None to declare.

Informed Consent

Not applicable.

Author Contributions

Metodi Popov is the attending physician, and described the case. Ivan Ivanov performed the laboratory tests and studied the literature. Valeri Velev is the attending physician, who summarized the case, and wrote the discussion.

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