Seronegative Autoimmune Hepatitis Following COVID-19

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The emergence of the coronavirus disease in 2019 (COVID-19) has spurred a flurry of scientific investigations into its pathophysiology, clinical manifestations, and potential long-term effects. While primarily a respiratory illness, COVID-19 has been found to impact various organs throughout the body, including the liver.

This article delves into the intriguing link between COVID-19 and autoimmune hepatitis, with a focus on the rare phenomenon of seronegative autoimmune hepatitis (SAH) occurring in the wake of COVID-19 infection.

The Intersection of COVID-19 and Hepatic Dysfunction

COVID-19 primarily targets the upper and lower respiratory tracts in humans, but its reach extends to nearly any organ system, including the liver. Approximately 14-53% of COVID-19 patients experience hepatic dysfunction, particularly those with underlying comorbidities [1]. Among this subset, some individuals have developed autoimmune hepatitis (AIH) as a result of COVID-19 infection or vaccination [2-5].

Autoimmune hepatitis typically presents with circulating autoantibodies, such as anti-nuclear antibody (ANA) and anti-smooth muscle antibody, which are characteristic of type 1 AIH. Type 2 AIH is associated with antibodies like anti-liver/kidney microsomal-1 and anti-liver cytosolic antigen type antibody [7].

However, approximately 10-20% of AIH patients do not exhibit these serologic markers, leading to the classification of seronegative AIH (SAH) [6].

Rare Cases of SAH Post-COVID-19

In the United States and elsewhere, only a handful of cases have been reported where individuals developed seronegative AIH following COVID-19 infection. One of the earliest instances was documented in India, where a patient exhibited right upper quadrant pain, jaundice, elevated liver enzymes, and high serum IgG levels.

This patient was empirically treated with steroids due to a strong suspicion of AIH, although a liver biopsy was not performed due to complications of acute respiratory distress syndrome (ARDS) [3].

In contrast, our case study presents a patient with normal IgG levels, highlighting the diverse manifestations of this phenomenon. To date, over 25 cases of AIH have been reported following COVID-19 mRNA vaccination, further emphasizing the need for vigilance in monitoring liver health post-vaccination [5].

Diagnosing AIH and SAH

AIH diagnosis typically involves the detection of autoantibodies and histologic findings. Histologically, AIH is characterized by plasma cell-rich lymphocyte-predominant hepatitis localized to the interface zone, often accompanied by confluent necrosis, which is associated with worse outcomes [8,9]. The clinical presentation of AIH varies widely, from asymptomatic cases to acute liver failure [5].

Diagnosing SAH can be challenging due to the absence of specific serologic markers. Clinicians often rely on the revised conventional diagnostic criteria and the simplified diagnostic criteria (SDC) to aid in diagnosis, with the latter demonstrating impressive specificity and sensitivity rates, both exceeding 90% [8].

Treatment and Outcomes

Standard AIH treatment involves immunosuppression with steroids and medications like azathioprine, which have been effective in 80-90% of patients. Steroid therapy is typically used to induce remission, followed by a transition to azathioprine for long-term maintenance of remission [7]. Importantly, immunosuppressive therapy has not been associated with worse outcomes in AIH patients affected by COVID-19, and most patients respond favorably to treatment [4].

The Broader Landscape: COVID-19 and Autoimmune Diseases

Beyond AIH, COVID-19 has been linked to various autoimmune diseases, including Guillain-Barre syndrome, autoimmune thyroid disease, and inflammatory bowel disease [9,10]. Extensive research across multiple medical specialties has explored these connections. Notably, rheumatologists have uncovered numerous publications on new-onset systemic and rheumatic autoimmune diseases related to COVID-19, underscoring the complex interplay between viral infection and the immune system [11].

The Mechanistic Nexus: ACE2 Receptors and Liver Injury

The mechanism of COVID-19 transmission involves the binding of the virus’s spike glycoprotein to angiotensin-converting enzyme 2 (ACE2) receptors, primarily located in the lungs. However, ACE2 receptors are also expressed in intestinal and cholangiocyte cells. Intriguingly, despite ACE2 receptors being found in only about 2.6% of hepatocytes, COVID-19-related hepatic injury often exhibits a hepatocellular pattern [12]. This has led to hypotheses about direct viral cytotoxicity from binding, contributing to liver damage [13].

Conclusion

The association between COVID-19 and autoimmune hepatitis, including the rare seronegative variant, has become more recognized over time. This evolving understanding underscores the importance of considering immune-mediated liver injury as a potential cause for elevated liver enzymes associated with COVID-19 infection, even when typical AIH antibodies are absent. Early recognition and treatment may lead to improved patient outcomes. However, further research is necessary to elucidate the intricate relationship between COVID-19 and autoimmune hepatitis fully. This ongoing exploration promises to shed more light on the complexities of viral infections and their impact on the immune system, paving the way for more effective treatments and prevention strategies.

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