Acute hepatitis due to infectious mononucleosis

Abstract

The syndrome of infectious mononucleosis is commonly seen with Epstein-Barr virus (EBV) infection. It may cause acute hepatitis, which is usually self-limiting and characterised by mildly elevated liver enzymes, but rarely jaundice. The patient being reported showcases EBV infection with jaundice, which is an uncommon scenario.

Background

Epstein-Barr virus (EBV) belongs to the family Herpesviridae and is responsible for infectious mononucleosis (IMN), which is characterised by fever, sore throat, lymphadenopathy and atypical lymphocytosis. It is usually an infection of the younger age groups. The transmission is by contact with oral secretions. The incubation period is from 4 to 6 weeks and the symptoms usually last for 2 to 4 weeks.¹ Acute hepatitis by EBV infectious mononucleosis (IMN) presents with mildly elevated transaminases, but jaundice is a rare scenario.

Case presentation

A 26-year-old male, engineering student, presented to the medicine department with a 5-day history of fever and myalgia. He also complained of mild abdominal discomfort, nausea and constipation. He had a history of varicella infection during childhood. He was not on any regular medications. There was no history of recent travel, illicit drug use or infective contacts. On examination, he was afebrile with vitals being stable. He was icteric (figure 1). Oral cavity showed mild pharyngeal congestion with a few aphthous ulcers (figure 2). There were no skin rashes or lymphadenopathy. His systemic examinations were normal with no signs of hepatic encephalopathy.

Figure 1.

Eyes showing icterus.

Figure 2.

Mild congested pharynx with aphthous ulcers.

Investigations

His complete blood counts showed leucocytosis (27 500 cells/mm³ with neutrophils 23% and lymphocytes 77%) and mild thrombocytopaenia (138 000 cells/mm³). His liver functions were deranged with total bilirubin: 7.4 mg/dL, direct bilirubin: 4.2 mg/dL, aspartate aminotransferase (AST): 332 IU/L, alanine aminotransferase (ALT): 294 IU/L, alkaline phosphatase (ALP): 175 IU/L and albumin: 3.0 g/dL. Plasma ammonium levels were mildly elevated (50 μmol/L). His renal functions, prothrombin time/international normalised ratio (PT/INR), activated partial thromboplastin time and electrolytes were normal. Smear for malarial parasite, Weil Felix test, leptospira serology, dengue serology and viral markers (HIV, hepatitis B virus surface antigen, anti-hepatitis C virus, hepatitis A virus immunoglobulin (Ig)M, anti-hepatitis E virus IgM, herpes simplex virus 1 and 2 IgM) were negative. Lactate dehydrogenase levels were normal (220 U/L). Blood cultures were sterile. Antinuclear antibody profile was negative. Ultrasound abdomen showed mild splenomegaly (13.6 cm). Echocardiography and chest X-ray were normal. His peripheral blood smear was suggestive of IMN with large granular lymphocytes and atypical lymphocytes (figure 3). Monospot (heterophile antibody) test was negative and throat swab culture was sterile. EBV viral capsid antigen (VCA) IgM and IgG were positive and EBV nuclear antigen (EBNA) IgG was negative. Cytomegalovirus (CMV) IgM and IgG were negative. Serum ceruloplasmin levels were normal.

Figure 3.

Peripheral smear showing large granular lymphocytes with atypical lymphocytes.

Treatment and outcome

He was managed mainly with intravenous fluids. Liver function tests and PT/INR were monitored every third day. By day 6 of admission, his complete blood counts and liver functions started showing a normalising trend (white cell count: 13 200 cells/mm³ with neutrophils 38% and lymphocytes 72%, platelets: 147 000 cells/mm³, total bilirubin: 4.8 mg/dL, direct bilirubin: 2.3 mg/dL, AST: 142 IU/L, ALT: 88 IU/L, ALP: 198 IU/L and albumin: 3.2 g/dL). Plasma ammonia levels also got normalised (28 μmol/L). He became completely asymptomatic and was discharged on day 12 with normal blood reports.

Discussion

Most of the childhood EBV infections are asymptomatic or present as mild pharyngitis with or without tonsillitis. However, the majority of adult EBV infections present as IMN. Fever, malaise, myalgia and fatigue are the common presenting complaints in adults. Pharyngitis, splenomegaly, lymphadenopathy and atypical lymphocytes are rare among elderly patients. Some patients may develop morbilliform or papular rash, erythema nodosum and erythema multiforme. The symptoms and signs of IMN along with their frequencies have been listed in table 1.¹

Table 1.

Symptoms and signs of IMN with their frequencies

Symptoms and signs	Frequency (%)
Sore throat	75
Malaise	47
Headache	38
Abdominal pain, nausea, vomiting	17
Chills	10
Lymphadenopathy	95
Fever	93
Pharyngitis/tonsillitis	82
Splenomegaly	51
Hepatomegaly	11
Rash	10
Periorbital oedema	13
Palatal enanthem	7
Jaundice	5

The blood investigations show lymphocytic leucocytosis with >10% atypical lymphocytes. The latter cells are enlarged lymphocytes with abundant cytoplasm and vacuoles. Neutropenia and thrombocytopaenia may also be seen. Liver function tests have raised aminotransferases and alkaline phosphatase. Serum bilirubin may be elevated. Direct hyperbilirubinaemia may be seen due to cholestatic hepatitis.² The heterophile antibody test with titres ≥40 fold is indicative of acute EBV infection. This test is positive in 40% of patients during the first week of infection and in 80%–90% during the third week, and remains positive for almost 3 months after the onset of illness. The titres of VCA IgM and IgG antibodies are raised in 90% of patients at the onset of disease. The seroconversion to EBNA positivity is also suggestive of acute infection. Early antigen diffuse antibodies are present in about 70% of patients with IMN, especially in those with severe disease. The presence of EBV DNA, RNA or proteins is valuable in demonstrating the association of the virus with several malignancies.¹

The treatment is mainly supportive measures with rest and analgesics. The condition is generally self-limiting. Excessive physical activity is discouraged during the first month in view of the possibility of splenic rupture. Prednisolone is used for prevention of airway obstruction in those with severe tonsillar hypertrophy, autoimmune haemolytic anaemia, thrombocytopaenia and haemophagocytic lymphohistiocytosis. Acyclovir has no significant clinical impact in the treatment of IMN but has been effective in oral hairy leukoplakia.¹ Ganciclovir has been used in the treatment of severe IMN hepatitis.³ The role of steroids in EBV hepatitis is controversial.^{4 5}

As mentioned earlier, liver function abnormalities may be seen in IMN, but symptomatic hepatitis is uncommon.⁶ The incidence of hepatitis in IMN is about 10% in young adults and about 30% in elderly.⁷ The elevation in aminotransferases levels are usually less than fivefold normal levels, and hyperbilirubinaemia is seen in up to 5% of patients.³ Cholestatic hepatitis has been observed⁸ and may be due to the effect of the virus on intrahepatic and systemic production of proinflammatory cytokines, which in turn interfere with the activity of both the sinusoidal and canalicular transporting systems. It may also occur as a result of biliary epithelial cell infection and high concentrations of enzyme-inhibiting autoantibodies against the antioxidative enzyme.^9–12 EBV may also trigger autoimmune hepatitis.¹³ Fulminant hepatic failure is a rare consequence and accounts for <1% of adult acute liver failure, holding a high case mortality rate.^{14 15} Other complications include splenic rupture, upper airway obstruction, meningitis and encephalitis, hemiplegia, psychosis, autoimmune haemolytic anaemia, myocarditis or pericarditis, pneumonia, genital ulcerations, vasculitis, bacterial superinfection and hepatitis.¹

About 90% of IMN is due to EBV, whereas 5%–10% is by CMV. The latter is the the most common cause for heterophile-negative IMN. The differential diagnosis includes HIV, rubella, lymphoma, viral hepatitis, herpes infection, streptococcal pharyngitis and toxoplasmosis.¹

Learning points.

• The presentation of infectious mononucleosis with jaundice is a rare scenario.

• The treatment of Epstein-Barr virus hepatitis is mainly supportive, as the condition is self-limiting.

• The use of antivirals and steroids is controversial.