Autoimmune hepatitis following Epstein-Barr virus infection: a diagnostic dilemma

Abstract

Epstein-Barr virus (EBV) infections frequently affect the liver and cause hepatitis. EBV is a well-known trigger of certain autoimmune diseases. There are few case reports showing the evidence of autoimmune hepatitis (AIH) following EBV infection. However, the diagnosis of AIH is very challenging in the setting of an acute infection. Here, we demonstrate a case of AIH following EBV infection in a patient ultimately recovered after receiving treatment for AIH.

Background

Epstein-Barr virus (EBV) is one of the most common human viruses and a well-known trigger of autoimmune diseases. Autoimmune liver disease, including autoimmune hepatitis (AIH), has a potential association with EBV infection. The diagnosis of AIH in the setting of acute EBV infection is very challenging, but the correct diagnosis is crucial since the treatments are very different.

Case presentation

A 42-year-old female patient with a history of cholelithiasis and cholecystectomy presented to the emergency department with 1 week of jaundice, itching and dark urine. She had flu-like symptoms with left upper quadrant pain 1 month prior, but an influenza test was negative. On admission, physical examination was remarkable for scleral icterus and jaundice. Laboratory data showed aspartate aminotransferase (AST) 373 IU/L (normal range: 30–120 IU/L), alanine aminotransferase (ALT) 912 IU/L (normal range: 10–60 IU/L), total bilirubin 14.1 mg/dL (normal range: 0.1–1.2 mg/dL) and direct bilirubin 9.8 mg/dL (normal range 0–0.2 mg/dL). CT scan of the abdomen and pelvis was unremarkable.

After admission, the patient had an extensive workup for acute hepatitis. Serological results were significant for positive antinuclear antibodies (ANA) and antismooth muscle antibodies (SMA) of 38 (normal range <20). The EBV-viral capsid antigen (VCA) IgG was 242 (normal range <18), EBV-VCA IgM >160 (normal range <36), EBV  Early D Antigen (EA(D)) IgG 23.4 (normal range <9), and EBV nuclear antigen (EBNA) IgG 295 (normal range <18). ALT, AST and total bilirubin continued fluctuating (figure 1). Liver biopsy showed inflammation within portal areas, positive EBV stain (figure 2).

Figure 1.

(A) The trending of ALT, AST and total bilirubin. The ALT and AST were improving at the time of hospital discharge, but the values trended up significantly to 777 and 1029 IU/L, respectively, at week 8 from hospital discharge. (B) The total bilirubin level also trended up significantly to 27.5 mg/dL at the same time. Prednisone was started on 24 April 2018. Azathioprine was started on 07 May 2018 when the prednisone was tapering off. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Figure 2.

(A) Liver biopsy H&E stain showed moderate inflammation within portal areas, consisting mostly of lymphocytes (circle). (B) Immunohistochemical stain showed positive Epstein-Barr virus (circle).

The patient was diagnosed with EBV hepatitis after excluding viral and autoimmune hepatitis, Wilson’s disease, primary biliary cirrhosis and primary sclerosing cholangitis. She was discharged home with symptomatic management.

She followed up in the outpatient clinic. Initially, ALT, AST and total bilirubin were trending down significantly during the first month. However, then her jaundice became worse, and she returned for further evaluation. ALT, AST and total bilirubin went up dramatically in week 8 (figure 1). The SMA titre was significantly elevated at 84 (normal range <20).

Differential diagnosis

Hepatitis A, hepatitis B, hepatitis C, Herpes Simpex Virus (HSV) hepatitis, Wilson’s disease, primary biliary cirrhosis and primary sclerosing cholangitis. The above entities were ruled out by normal serology and negative biopsy.

Autoimmune hepatitis was not considered given the biopsy did not show definitive evidence of it. However, it could not be totally ruled out given the fact of borderline elevation of anti-SMA.

EBV hepatitis was diagnosed initially based on positive serologies and biopsy as noted.

Autoimmune hepatitis was diagnosed afterwards given patient’s symptoms and liver function were worsening after discharged. Anti-SMA was elevated significantly after recheck.

Treatment

She was started empirically on oral prednisone after reconsideration of autoimmune hepatitis because of the increasing liver enzymes. At the follow-up appointment, after discussing the side effects of corticosteroid as a long-term treatment, she preferred an alternative agent. Interestingly, the thiopurine methyltransferase (TPMT) test result was consistent with a heterozygous genotype. This group has relatively low risk of bone marrow toxicity for azathioprine; therefore, she was initiated on azathioprine 50 mg daily with tapering dose of prednisone.

Outcome and follow-up

Her symptoms eventually resolved and liver enzymes normalised by 2 months after receiving the treatment of azathioprine (figure 1). She tolerated azathioprine well. She continues following up in the outpatient clinic to monitor complete blood counts.

Discussion

The association between EBV and AIH has been reported previously.^1–3 There are a few case reports showed AIH following by EBV infection.^{2 3} It was proposed that EBV triggers autoreactive CD4+ T lymphocytes recognising a liver-specific autoantigen.¹ In fact, EBV can cause acute hepatic injury known as EBV hepatitis. Positive EBV-VCA IgM, EBV VCA IgG and EBV EA (D) IgG and abnormal liver function are the hallmark of diagnosis. To diagnose AIH, ANA is usually positive, and SMA titre is greater than 40.⁴ Our patient presented with severe acute hepatic injury of hepatocellular pattern. The borderline elevation of SMA was inconclusive for AIH. The positive EBV antibody and liver biopsy result suggested EBV hepatitis at the time. In this case, it was difficult to distinguish autoimmune hepatitis from acute EBV hepatitis. Hence, the patient was treated for EBV hepatitis with supportive care. However, the rebound of liver enzymes after discharge and increasing SMA titre prompted us to reconsider AIH as the diagnosis. As reported previously, EBV infection may be the trigger for AIH.¹ The treatment of AIH is corticosteroid or azathioprine plus tapering corticosteroid. The patient received oral prednisone initially. The therapy was changed to azathioprine when tapering off the corticosteroid due to the concern of the side effects of long-term corticosteroid use. We tested TPMT to make sure that patient did not have TPMT deficiency before starting azathioprine to avoid the severe bone marrow toxicity.⁵ The TPMT activity was in the range suggesting heterozygous genotype, and about 40%–70% are able to tolerate the full dose of azathioprine.⁶ Our patient was started on azathioprine 50 mg daily with tapering dose of prednisone. Her liver function test returned to the normal range. She tolerated azathioprine therapy well without signs of bone marrow toxicity. She continues following up in the outpatient clinic.

Patient’s perspective.

I went to the emergency department of Gwinnett Medical Center in February 2018 due to worsening yellow skin. I was admitted to the hospital after I was told that my liver function was severely damaged. I received some blood tests and a liver biopsy to figure out the cause of my liver dysfunction. After gathering the results from those tests, I was told that I have ‘EBV hepatitis’ which is a benign condition, and my body will control the infection by itself. At the time of being released from the hospital, I felt a bit better. However, the yellowish discolouration was still obvious. A few weeks later, my liver enzymes went up again. At the time, I was told that I have autoimmune hepatitis. My doctor explained everything to me in detail. He also shared the treatment plans with me and my family. I started feeling better significantly after taking the medicine he prescribed. I went to the clinic to check my liver function afterwards. The liver enzymes returned to normal range. The yellowish discolouration of my skin also disappeared. Everyone who was involved in my care, the doctors, nurses, medical assistants, was awesome! They provided greatest care I have ever had!

Learning points.

• Autoimmune hepatitis can be triggered by acute Epstein-Barr virus (EBV) infection.

• Under the condition of acute EBV infection, if patient’s liver enzymes are still elevated after a period of time and autoimmune hepatitis is still suspected, antismooth muscle antibody should be rechecked.

• The thiopurine methyltransferase should be tested before starting azathioprine. Patients with homozygous low thiopurine methyltransferase will have high-risk bone marrow toxicity after taking azathioprine.

• Azathioprine can be started safely to treat autoimmune hepatitis with borderline low thiopurine methyltransferase, but complete blood counts should be monitored closely.