Epstein-Barr Virus And Autoimmune Hepatitis

Overview

Epstein-Barr Virus (EBV) is a common virus that is predicted to infect around 95% of the healthy population.¹ It is a type of herpes virus that spreads through saliva and bodily fluids.² EBV is the virus responsible for mononucleosis or glandular fever. EBV has also been associated with other conditions such as chronic fatigue syndrome, multiple sclerosis, encephalitis, Alzheimer’s diseases as well as various cancers and autoimmune diseases.³

Autoimmune hepatitis is a rare condition where the body’s immune system damages its own liver cells.⁴ Autoimmune hepatitis is a long-term chronic condition that manifests with symptoms of fatigue, itching, yellowing of the skin and eyes and generally feeling unwell.⁴ If untreated, it can lead to liver scarring or cirrhosis. EBV is implicated in many autoimmune diseases and may have a causative link to autoimmune liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune hepatitis.⁵ Here the possible link between EBV and autoimmune hepatitis will be explored further. 

Epstein-Barr Virus

EBV is a herpes virus that is transmitted through bodily fluids. An EBV infection begins in the epithelial cells of the throat and then spreads to the B cells (a type of immune cell found throughout the body) that are resident in the oral canal.⁶ Most of the population becomes infected during childhood. Childhood infections are mostly asymptomatic whereas infections that occur after childhood often develop into mononucleosis (glandular fever). The key symptoms of mononucleosis include fever, fatigue and sore throat.⁶

It is predicted that 95% of the population carry EBV because after the initial EBV infection, the virus lies dormant in the B cells of your body, this is known as latent infection.⁶ When cellular immunity is weakened the virus can reactivate. These conditions include stress, infections, the presence of chemical agents, and the immunosuppressive results of cancers and autoimmune diseases.⁷ 

When EBV reactivates the symptoms are largely similar to before, with virus-like symptoms. However chronic infection and reactivation of EBV has been correlated with autoimmune conditions and cancers such as Burkitt’s lymphoma, Hodgkin’s disease, nasopharyngeal carcinoma, gastric adenocarcinoma⁷ as well as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes and well as many others.⁸

Autoimmune hepatitis

Hepatitis describes inflammation of the liver. There are many different types and causes of hepatitis and it can be both acute (short-term) and chronic (long-term). Hepatitis is usually caused by viral infections or damage to the liver from drinking alcohol. Chronic cases of hepatitis can cause liver scarring (cirrhosis), loss of liver function and in some cases liver cancer.⁹

Autoimmune hepatitis is a form of hepatitis where the damage to the liver is caused by the patient’s own immune system. This damage is mainly from autoreactive CD4+ T cells and liver-specific autoantigens.⁵ Patients with autoimmune hepatitis experience symptoms including fatigue, itching, yellowing of the skin and eyes and generally feeling unwell.⁴ Treatment course is usually immunosuppressants, which are drugs that reduce the activity of the immune system, this will reduce the damage to the liver, preventing scarring and long term liver failure. ⁴ 

Whilst much about the pathogenesis of autoimmune hepatitis is not known there are a few hypotheses that aim to try and answer the question of how this condition arises. Firstly there are some genetic variants that people may possess that can predispose them to autoimmune hepatitis.¹⁰ There is also the hypothesis of molecular mimicry which suggests that after a person has become infected with certain viruses or bacteria, the immune system tries to recognise these foreign invaders, but similarities between the proteins on the virus/bacteria and the proteins found in the liver mean that the immune system mistakenly attacks the liver. Finally there are also several drugs such as minocycline, some statins and nitrofurantoin etc which may also provide a cause for autoimmune hepatitis. The current theory is that drug metabolites may stimulate the production of antibodies that target the proteins of the liver.¹⁰ There are commonly two types of autoimmune hepatitis depending on what type of autoantibodies are present in the patient. Autoantibodies are antibodies that target proteins of your own healthy cells, they are characteristic of autoimmune diseases.⁵ Depending on which proteins your autoantibodies are targeting this will classify your autoimmune hepatitis as either type 1 or type 2.⁵

A possible link between EBV and autoimmune hepatitis?

Whilst Epstein-Barr virus has been implicated in many autoimmune diseases, there is not conclusive evidence yet to say that EBV can cause autoimmune hepatitis.⁵ However there have been several reported cases of autoimmune hepatitis arising after EBV infection.^11,12,13,14

A paper by Rigopoulou et al, presents the evidence for and against EBV being a trigger for autoimmune hepatitis.⁵ Of course there have been reports of patients developing autoimmune hepatitis following an EBV infection and patients with autoimmune hepatitis have been shown to have evidence of EBV infections in their serum. However, it is also important to consider that the prevalence of EBV is high but the prevalence of autoimmune hepatitis is relatively low, suggesting there must be other factors at play to lead to development of the liver disease. There is also a lack of conclusive evidence relating to exactly what molecular mechanisms are causing autoimmune hepatitis to arise from EBV infections.⁵

EBV is a common culprit for autoimmune diseases because it persists in a patient’s immune cells and alters the immune response. EBV also inhibits cell death or apoptosis of immune cells which may play a role in the exacerbated immune responses seen. For patients with type 2 autoimmune hepatitis they may have some autoantibodies targeting a liver enzyme called CYP2D6. EBV contains two proteins, EBNA and BVRF1, that are similar to this enzyme and therefore could be responsible for the generation of antibodies against it, however this has yet to be conclusively proven. 

As with most diseases it is also important to consider the genetic component that may play a role. Familial studies by Vento et al, showed that out of 13 family members of patients with autoimmune hepatitis, 7 became infected with EBV and got mononucleosis. 2 of these 7 developed autoimmune hepatitis and both of these patients had pre-existing T cell defects- suggesting that both the genetic predisposition and the viral infection were involved in the development of autoimmune hepatitis.¹¹

Conclusion

Epstein-Barr virus is a common virus that infects most of the population, generally it leaves most people unaffected or with a simple case of mononucleosis, however sometimes it can lead to other conditions like cancers and autoimmune diseases. Whilst autoimmune hepatitis is a relatively rare condition it has significant impacts on a patient’s life and there is no definitive cure, only treatment options to reduce the effects. Cases of autoimmune hepatitis have been recorded following EBV infections and there have been various studies and hypotheses into how this may arise, however there is yet to be definitive proof of a cause. Although EBV is a fairly common disease and in most cases will not cause further issues, if an autoimmune disease is to arise it is important to get a prompt diagnosis. Early diagnosis and interventions for patients with autoimmune hepatitis will reduce the damage to the liver before significant and permanent damage is caused. As more research is conducted into this area it is hoped that the link between the two conditions may become more clear.