A rare presentation of infectious mononucleosis: cholestatic hepatitis with hyperbilirubinemia

Abstract

Introduction

Epstein-Barr virus infection with mononucleosis is the most common presentation in young adults. Most infections are self-limited, although in a few cases complications can include serious conditions such as lymphoproliferative disorders or in less severe cases, mild hepatitis.

Case report

We present an unusual case of a young male with no liver disease, who presented with markedly elevated cholestatic pattern hyperbilirubinemia, as well as hepatitis. The patient responded well to symptomatic treatments, with spontaneous improvement of the hyperbilirubinemia and transaminitis.

Conclusions

Epstein-Barr virus mononucleosis can frequently present with mild elevation of transaminases, but very rarely can have marked elevation of bilirubin, which may make clinicians doubt that the infection is the sole culprit of the process.

Introduction

Infectious mononucleosis is caused by the Epstein-Barr Virus (EBV), and is usually characterized by the presence of fever, sore throat, adenopathy, generalized weakness and hepatosplenomegaly. The infection can occur at any age; however, mononucleosis is most common in age groups between 15 and 30 years of age. Symptomatic disease is more likely to occur in older patients, and the odds of severe symptoms positively correlate with age.¹ Most infections resolve without treatment with an overall good prognosis, with symptoms usually lasting for 2 to 4 weeks. In a few cases, however, EBV infection can have mild complications such as hepatitis or hepatomegaly, or severe complications such as lymphoproliferative disorders or liver failure, though these are fortunately rare.² Although EBV can cause mild elevations in liver enzymes, the presence of jaundice is rather uncommon.

Case report

A 25 year-old male with ADHD (attention deficit hyperactivity disorder) presented to the hospital with complaints of yellowish discoloration of the skin. The onset of his symptoms was 2 weeks previously. Initially, the patient experienced headache, fever up to 102 to 103°F (38.9 to 39.4°C), night sweats and dizziness. He performed COVID-19 tests twice at home which were negative. He had a virtual encounter with his primary care physician (PCP), who recommended symptomatic treatment with acetaminophen, ibuprofen, as well as cefuroxime for probable sinusitis. Five days later, the patient called his PCP for further instructions due to the continuous fever, now up to 103.8°F (39.9°C). He was prescribed azithromycin by his PCP, as well as amoxicillin-clavulanic acid from another healthcare provider. About 3 days after the new antibiotics were prescribed, he started to experience a sore throat which progressed despite being on antibiotic therapy. One to two days after the sore throat occurred, the patient noticed yellowish discoloration of the skin, as well as a change of the color of his urine to dark brown, nausea and vomiting. He voiced these new concerns with his PCP and was instructed to go to the emergency department.

As a social history, the patient denied any prior sexually transmitted disease and reported sexual activity with 1 female partner for the past 1 year. He denied current or prior smoking, alcohol abuse, or illicit drug use. He did not have any recent travel. His only regular medication was amphetamine with dextroamphetamine for his ADHD. On admission, he had a temperature of 100.3°F (37.9°C), heart rate of 102 bpm. Otherwise, he was vitally stable. On examination, he had icterus and a yellowish discoloration to his skin and conjunctiva. A generalized erythematous maculo-papular rash was also present, more on his upper extremities. Oral mucus membranes were moist. The patient did have bilateral pharyngeal erythema with symmetric tonsillar hypertrophy and exudates. Submental lymph nodes were palpable. On the abdominal exam, hepatosplenomegaly was appreciated. Laboratory results (Table 1) on admission were significant for mild leucocytosis (WBC 11.09 k/mcL) with lymphocytosis (7.49 k/mcL) and 19% of atypical lymphocytes. Transaminitis was also noted with alanine aminotransferase (ALT) 556 IU/L, aspartate aminotransferase (AST) 377 IU/L and alkaline phosphatase (ALP) 571 IU/L. Bilirubin was also elevated at 9.3mg/dL. Urinalysis showed no pyuria. Acetaminophen level in the serum was low at 10 mcg/mL. All hepatitis serologies, including hepatitis A virus IgM, hepatitis B virus core antibody IgM, hepatitis B virus surface antigen, hepatitis C virus antibody and hepatitis E virus IgG and IgM were negative. The streptococcal antigen test was negative. HIV screen, Chlamydia and Gonorrhoea urine PCR and syphilis screen were all negative. Monospot test which detects the antibody produced in response to the EBV infection was positive. Anti-VCA IgM was positive indicating early phase of EBV infection. Anti-VCA IgG was negative. Antibody to EBV nuclear antigen was negative, again indicating that this was most likely an acute EBV infection. CT scan of abdomen and pelvis with intravenous contrast showed hepatosplenomegaly with no inflammatory changes, CT scan of the neck showed scattered subcentimeter lymph nodes but no other acute findings. Chest X-ray was unremarkable. Ultrasound of abdomen showed hepatomegaly likely due to underlying hepatocellular disease. No focal intrahepatic lesions or biliary ductal dilatation was noticed. Contracted gallbladder with no wall thickening or sonographic findings to suggest cholecystitis were present. No pericholecystic fluid was found. The patient was admitted for hepatosplenomegaly with hyperbilirubinemia and transaminitis likely due to infectious mononucleosis. The patient also had diffuse maculopapular erythematous rash likely due to administration of amoxicillin-clavulanic in the setting of mononucleosis.

Table 1.

Clinical laboratory results

Parameter	Reference range	On admission	At discharge	At follow-up visit
White-cell count (per μL)	4,000-11,000	11,090‡	6,160	—
Red-cell count (per μL)	4,500,000-8,900,000	4,550,000	4,510,000	—
Absolute neutrophil count (per μL)	1,800-7,500	2,680	1,480†	—
Absolute lymphocyte count (per μL)	1,000-5,000	7,490	3,940	—
Platelet count (per μL)	150,000-400,000	256,000	277,000	—
Hemoglobin (g/dL)	13.5-17.5	13.8	13.1†	—
Hematocrit (%)	41.0-53.0	39.7†	40.2†	—
Sodium (mmol/L)	135-145	126†	133†	—
Potassium (mmol/L)	3.5-5.2	4.3	4.4	—
Chloride (mmol/L)	98-109	93†	99	—
Calcium (mg/dL)	8.4-10.5	8.6	8.7	—
Carbon dioxide (mmol/L)	23-34	23	23	—
Anion gap (mmol/L)	4-14	10	11	—
Glucose (mmol/L)	70-200	112	110	—
Blood urea nitrogen (mg/dL)	8-20	13	10	—
Creatinine (mg/dL)	0.70-1.50	1.06	1.08	—
Total protein (g/dL)	6.2-8.1	6.8	5.9†	—
Albumin (g/dL)	3.5-5.0	3.1†	3.0†	—
Total bilirubin (mg/dL)	0.0-1.5	9.3‡	9.9‡	4.6‡
Direct bilirubin (mg/dL)	0.0-0.4	—	7.1‡	1.8‡
Alanine aminotransferase (U/L)	0-45	556‡	446‡	295‡
Aspartate aminotransferase (U/L)	0-45	377‡	279‡	111‡
Alkaline phosphatase (U/L)	20-120	571‡	598‡	382‡
Prothrombin time (sec)	12.2-14.9	12.8	11.8†	—
International normalized ratio	0.9-1.1	1.02	0.89†	—
Hepatitis A IgM	negative	negative	—	—
Hepatitis B core IgM	negative	negative	—	—
Hepatitis B surface antigen	negative	negative	—	—
Hepatitis C antibody	negative	negative	—	—
Hepatitis E IgM and IgG	negative	negative	—	—
Acetaminophen level (mcg/mL)	<20	<5	—	—

^‡Levels increased above the laboratory’s normal reference range.

^†Levels decreased below the laboratory’s normal reference range.

He was treated conservatively with IV fluids and non-steroidal anti-inflammatory drugs for fever. The patient improved symptomatically and was subsequently discharged with instructions to avoid contact sports.

At a follow up visit with his PCP 2 days after the discharge, a liver function panel was repeated and showed a marked decrease of the bilirubin level from 9.9 mg/dL (at the time of discharge) to 4.6 mg/dL, and a decrease in alkaline phosphatase (ALP) (382 IU/L), aspartate aminotransferase (AST) (295 IU/L), and alanine aminotransferase (ALT) (111 IU/L). At his regular follow up for his ADHD more than 2 months after the discharge, he was reported to be feeling well.

Discussion

EBV infection is common in young adults and adolescents, and is primarily spread by contact with oral secretions. In rare instances, primary EBV infection can also be transmitted by blood transfusion, solid organ transplantation or hematopoietic stem cell transplantation.¹ Most cases improve without any treatment with very good prognosis; however, in some cases the infection can have several different complications ranging from mild hepatitis to lymphoproliferative disorders and in rare occasions, acute liver failure. Cholestasis and jaundice are relatively frequent occurrences in EBV infection. Jaundice can be as high as 30% in patients aged 35 or older, but as low as 3% in patients less than 35 years-old. There are a few mechanisms suggested which cause cholestasis. One theory suggests that the virus, releasing pro-inflammatory cytokines, interferes with the activity of both the sinusoidal and canalicular transporting systems causing cholestasis.^3-4 Another theory suggests that it is caused by lipid peroxidation and consequent free radical production causing cytotoxic effects on hepatocytes.⁵

Our patient’s laboratory values were suggestive of cholestatic hepatitis, which is a rare presentation of EBV. Cholestatic hepatitis secondary to EBV has been reported mainly in adults. In the majority of the cases we reviewed, the patients had good outcomes with symptomatic treatment.^6-8 There was one case from Spain, which had higher bilirubin level than most of the reported cases. He was a 40 year-old with a medical history of steatosis, who presented with a bilirubinemia of 8.2 mg/dL, a similar level to our patient. Due to the persistence of his high bilirubin level after one month, a liver biopsy was done, which showed inflammation and lymphocytes with positive FISH EBVR (Epstein-Barr virus encoded RNA). Further treatment and outcome after this diagnosis was not described in the case report though. In our case, hyperbilirubinemia improved quickly, with levels returning to almost normal 9 days post-discharge. Another interesting case report from Greece described a case of infectious mononucleosis presenting as acalculous cholecystitis with marked hyperbilirubinemia with predominance of direct bilirubin.⁹ The patient had tenderness on the upper right quadrant, and the ultrasound of the abdomen reported thickening of gallbladder wall (4.5 mm). In our patient, limited ultrasound of the abdomen revealed contracted gallbladder with no wall thickening or sonographic findings to suggest cholecystitis making the diagnosis of acalculous cholecystitis unlikely. Other potential factors which could have caused the liver injury are side effects from medications. The patient had no prior history of elevated liver enzymes. He was taking ibuprofen and acetaminophen for symptomatic management of fever and sore throat prior to admission. Acetaminophen toxicity or overdose is a known cause of liver injury, however our patient endorsed that he took it as prescribed by his primary care physician and the chances of him surpassing the recommended dose of up to 4 g/day were unlikely. Acetaminophen levels were also low at the time of admission. Clinically significant hepatic injury from ibuprofen is very rare. Liver injury from amoxicillin-clavulanic acid is well described in literature and the onset of injury can range anywhere from a few days to about 8 weeks after exposure to the drug (the average is around 3 weeks). Our patient presented with marked transaminitis 3-5 days from initiation of therapy. Although drug-induced hepatitis could be a possibility, it is unlikely since hepatic injury from amoxicillin-clavulanic acid is more common in the elderly and after multiple courses, which is not in our case.

Most cases of mononucleosis are self-limiting and the treatment is supportive. Evidence for the benefit of corticosteroids in uncomplicated cases is insufficient,⁷ and these can even have harmful effects on host immunity and produce larger reservoirs of latently infected cells. A short course of steroids is indicated in some cases of complicated infectious mononucleosis, such as extreme tonsillar enlargement with impending airway obstruction, hemolytic anemia, thrombocytopenia, and aplastic anemia. In cases of cholestatic hepatitis,^4-6 almost all of the cases we reviewed were treated conservatively with a good outcome, with the exception of one case of an elderly patient who presented with encephalopathy and received intravenous immunoglobulin, not for the hepatitis but for central nervous system involvement.⁵ Unusual presentation of mononucleosis can also lead to surgical management. There is a tragic case of a 15-year-old female who presented with marked hyperbilirubinemia, elevated transaminases, and gallbladder with thickened wall.¹⁰ She was diagnosed with acute cholecystitis and underwent cholecystectomy. The patient unfortunately died shortly after the surgery. Post-mortem blood test found elevated levels of EBV IgM antibody with autopsy diagnosis of active EBV infection with moderately severe hepatitis and disseminated intravascular coagulation (DIC). This case teaches the clinician the importance of taking into account all possibilities and having a broad differential diagnosis in mind so as to to not miss an unusual presentation of a common disease. Table 2 summarizes the epidemiology, clinical features, complications, main laboratory findings and treatment options for EBV infection. In our case, the patient improved spontaneously and he continued to feel better at follow up appointment 2 months after the discharge.

Table 2.

Epstein-Barr virus (EBV)

Epidemiology	• Common infection with a high lifetime prevalence • Most frequently seen in children and adults • Spreads most commonly through oral secretions like saliva. Can also spread through blood transfusion, sexual contact and organ transplantation.
Clinical Features	Common presenting symptoms: • Fever, rash, sore throat, malaise, fatigue • Lymphadenopathy • Abdominal pain • Hepatosplenomegaly
Complications	• Neurologic: encephalitis, seizures, acute psychosis, Guillain-Barré syndrome, optic neuritis • Cardiac: myocarditis, pericarditis • Gastrointestinal: acalculous cholecystitis, cholestatic hepatitis, hyperbilirubinemia, splenic rupture, liver failure • Renal: interstitial nephritis, glomerulonephritis • Respiratory: pneumonia, upper airway obstruction • Hematologic: anemia, thrombocytopenia, leukopenia, lymphoproliferative disorders, Burkitt’s and Non-Hodgkin’s lymphoma.
Laboratory findings	• Elevated liver enzymes are common in EBV • Presence of hyperbilirubinemia and cholestatic hepatitis is rather uncommon. • Lymphocytosis
Treatment	• Usually supportive or conservative management especially in uncomplicated cases. • Short course of steroids should only be reserved for complicated cases of mononucleosis. • Antivirals have not been found to reduce the severity or duration of the disease. They do appear to decrease the oropharyngeal virus shedding.

Conclusions

Cholestatic hepatitis with hyperbilirubinemia is an uncommon presentation of EBV infection and has been reported mainly in adults. Clinicians should be aware that most patients usually respond well to conservative or symptomatic treatment.