ABSTRACT

Autoimmune hepatitis (AIH) is a complex condition with unclear origins, involving genetic susceptibility and environmental triggers that lead to immune system dysfunction. We report a case of a pregnant woman from a mosquito-borne disease-endemic area who presented jaundice, abdominal pain, and pruritus, complicated by acute liver failure. Immunological markers showed AIH triggered by dengue virus infection, which was confirmed by a positive IgM test. Treatment with supportive care followed by steroids and azathioprine resulted in favorable outcomes, averting the need for a liver transplant. Although AIH can be triggered by viruses, the role of dengue in its pathogenesis remains poorly understood. Regular clinical monitoring is vital for managing AIH, particularly during pregnancy, due to variable immune status and treatment responses. Further research is necessary to understand the link between dengue infection and AIH. Individualized treatment strategies are crucial, especially during pregnancy, in order to ensure favorable outcomes.

Keywords:
Hepatitis, autoimmune; dengue virus; pregnant; liver failure, acute; infections

INTRODUCTION

Dengue is endemic in several regions of Peru, particularly in the northern regions and the Amazon, where high morbidity and mortality rates are reported each year ¹1. Cabezas C, Fiestas V, García-Mendoza M, Palomino M, Mamani E, Donaires F. Dengue en el Perú: a un cuarto de siglo de su reemergencia. Rev Peru Med Exp Salud Publica. 2015;32(1):146-56.^,22. Luque N, Cilloniz C, Pons MJ, Donaires F, Albornoz R, Mendocilla-Risco M, et al. Características clínicas y epidemiológicas de las muertes por dengue durante un brote en el norte del Perú. Rev Peru Med Exp Salud Publica. 2023;40(1):67-72. doi: 10.17843/rpmesp.2023.401.12148.
https://doi.org/10.17843/rpmesp.2023.401... . The main vector of transmission is the Aedes aegypti mosquito. Efforts are currently underway to improve public education and public awareness regarding dengue prevention ³3. Gutierrez EL, Piazza M, Gutierrez-Aguado A, Hijar G, Carmona G, Caballero P, et al. Uso de la evidencia en políticas y programas de salud aportes del Instituto Nacional de Salud. Rev Peru Med Exp Salud Publica. 2016;33(3):580-584. doi: 10.17843/rpmesp.2016.333.2308.
https://doi.org/10.17843/rpmesp.2016.333... . However, dengue remains a public health challenge worldwide. In 2023, the World Health Organization (WHO) ⁴4. World Health Organization. Disease Outbreak News; Dengue - Global situation. [citado 4 de abril de 2024]. Disponible en: https://www.who.int/emergencies/disease-outbreak-news/item/2023-DON498.
https://www.who.int/emergencies/disease-... reported, in the Americas region, which includes Peru, Brazil, Mexico, and Colombia, a total of 4.1 million suspected dengue cases, 6710 severe cases, and 2049 deaths. The African regions accumulated 171,991 dengue cases and 753 deaths; the Southeast Asia region accumulated 308,167 dengue cases and 1745 deaths. Other regions, such as the Eastern Mediterranean, Europe, and the Western Pacific, also face dengue morbidity and mortality. Currently, dengue is a persistent public health challenge due to periodic epidemiological outbreaks, putting great pressure on health systems due to its high infection rates.

Dengue can have a variety of symptoms, with fever and skin lesions being the most common ⁵5. Dengue guidelines, for diagnosis, treatment, prevention and control. World Health Organization: 2009. [citado 4 de abril de 2024]. Disponible en: https://www.who.int/publications/i/item/9789241547871.
https://www.who.int/publications/i/item/... . However, it can also affect the digestive system, causing symptoms such as abdominal pain, jaundice, hepatitis and, in severe cases, acute liver failure ⁶6. Juneja D, Jain R, Nasa P. Dengue induced acute liver failure: A meta summary of case reports. World J Virol. 2024; 13(1): 91457. doi: 10.5501/wjv.v13.i1.91457.
https://doi.org/10.5501/wjv.v13.i1.91457... . Distinguishing the symptoms of dengue and autoimmune hepatitis (AIH) is crucial, because they may overlap. Following dengue infection, the immune system may generate autoreactive T cells capable of reacting to liver antigens, causing an abnormal autoimmune response. However, unlike AIH, specific biomarkers such as ANA, LKM-1 and ASMA are not typically found in dengue infection. We report the first case in Peru and the second worldwide ⁷7. Jagtap AB, Chirant S, Chaitanya V, Lall B, Porwal YC. Autoimmune hepatitis unmasked by dengue infection - An unexplored and rare association. Trop Doct. 2023;53(1):181-182. doi: 10.1177/00494755221130127.
https://doi.org/10.1177/0049475522113012... of a patient who debuted with AIH and acute liver failure, triggered by dengue virus infection.

Understanding the symptoms, diagnosis and treatment of mosquito-borne infections is essential. However, it is challenging to diagnose cases like our patient. Therefore, it is crucial to raise differential diagnoses when the clinical presentation does not follow the typical pattern. Existing literature highlights the potential risk of developing immunological diseases as a result of viral infections ⁸8. Vento S, Guella L, Mirandola F, Cainelli F, Di Perri G, Solbiati M, et al. Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet. 1995;346(8975):608-609. doi: 10.1016/s0140-6736(95)91438-2.
https://doi.org/10.1016/s0140-6736(95)91... ^,99. Hong JK, Chopra S, Kahn JA, Kim B, Khemichian S. Autoimmune hepatitis triggered by COVID-19. Intern Med J. 2021;51(7):1182-1183. doi: 10.1111/imj.15420.
https://doi.org/10.1111/imj.15420... . In addition, IAH is a complex condition characterized by unclear mechanisms involving the interaction between genetic components and environmental triggers. This complex condition emphasizes the importance of correct diagnosis and treatment to prevent future complications ¹⁰10. Olivas I, Rodríguez-Tajes S, Londoño MC. Autoimmune hepatitis: Challenges and novelties. Hepatitis autoinmune: retos y novedades. Med Clin (Barc). 2022;159(6):289-298. doi: 10.1016/j.medcli.2022.04.004.
https://doi.org/10.1016/j.medcli.2022.04... .

CASE REPORT

Patient information

We present the case of a 34-year-old woman, 26 weeks pregnant, from the city of Iquitos, in the Amazon region of Peru. She went to the emergency room of the Regional Hospital of Loreto, with a persistent condition of two weeks, characterized by reduced appetite, abdominal pain, jaundice, pruritus and headache. There was no significant history and she did not present any complications during her gestation.

Clinical findings

Physical examination showed jaundice of the skin and mucous membranes and pain in the right hypochondrium on palpation. Gynecological examination showed a uterine height of 22 cm and a fetal heart rate of 150 beats per minute, accompanied by fetal movements.

Timeline

Laboratory tests confirmed the presence of IgM antibodies and the absence of IgG antibodies, indicating active dengue virus infection (Table 1). The diagnosis was confirmed by the hospital’s infectious disease service. During this period, the DENV-2 serotype was the most prevalent in the city of Iquitos. The patient was diagnosed with hepatitis caused by dengue virus and transferred to a tertiary level hospital Edgardo Rebagliati Martins in Lima, to be treated in the Hepatology Service.

Diagnostic evaluation

After one month of persistent symptoms, when she was in the Hepatology Service, her clinical condition worsened, presenting alteration of the sensorium and acute liver failure. The King’s College criteria ¹¹11. McPhail MJ, Farne H, Senvar N, Wendon JA, Bernal W. Ability of King's College Criteria and Model for End-Stage Liver Disease Scores to Predict Mortality of Patients With Acute Liver Failure: A Meta-analysis. Clin Gastroenterol Hepatol. 2016;14(4):516-e45. doi: 10.1016/j.cgh.2015.10.007.
https://doi.org/10.1016/j.cgh.2015.10.00... were applied, and the patient met the criteria for acute liver failure, so she was admitted to the liver transplant list. Due to her deteriorating condition, she was transferred to the intensive care unit (ICU) for strict monitoring.

Therapeutic intervention

It was suspected that the acute liver failure could be a consequence of AIH, triggered by acute dengue virus infection. Immunological markers were dosed and found to be increased, confirming the suspicion. Treatment started with methylprednisolone 50 mg per day. The response to treatment was positive at clinical and laboratory level (Figure 1). Due to the substantial improvement of the patient, it was decided to remove her from the transplant list. However, the pregnancy was complicated with premature rupture of membranes and acute fetal distress, requiring an emergency cesarean section at 29 weeks gestation. The procedure resulted in a healthy, uncomplicated newborn with an adequate Apgar score. But due to prematurity, she remained four weeks in the neonatal intensive care unit, showing a stable and promising recovery. The patient continued receiving intravenous corticoids, and all her laboratory parameters stabilized, so it was decided to switch to oral treatment with an initial prednisone dose of 50 mg per day, which gradually decreased to 10 mg before discharge (Figure 1). All her laboratory and imaging controls were normal and no additional complications were found. The patient was discharged on a maintenance dose of prednisone 5 mg and azathioprine 50 mg per day.

Follow-up and results

One month after her discharge, the patient returned for her follow-up appointment, she showed no symptoms and normal transaminase and bilirubin levels. She was instructed to continue treatment with prednisone and azathioprine. Furthermore, the newborn remained healthy and did not experience any additional complications.

DISCUSSION

Autoimmune hepatitis (AIH) is a complex disease influenced by genetic, epigenetic, immunological and environmental factors. It predominantly affects women in a bimodal presentation ¹²12. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015;63(4):971-1004. doi: 10.1016/j.jhep.2015.06.030.
https://doi.org/10.1016/j.jhep.2015.06.0... . Although the exact mechanism remains unknown, it is hypothesized that the production of autoreactive T cells acts against self-tolerance to hepatic autoantigens. In addition, overexpression of Th1 and Th17 cells, which mediate the proinflammatory response, plays an important role in its pathogenesis ¹³13. Sirbe C, Simu G, Szabo I, Grama A, Pop TL. Pathogenesis of Autoimmune Hepatitis-Cellular and Molecular Mechanisms. Int J Mol Sci. 2021;22(24):13578. doi: 10.3390/ijms222413578.
https://doi.org/10.3390/ijms222413578... . Some studies report that viral infections can trigger this immune response ⁷7. Jagtap AB, Chirant S, Chaitanya V, Lall B, Porwal YC. Autoimmune hepatitis unmasked by dengue infection - An unexplored and rare association. Trop Doct. 2023;53(1):181-182. doi: 10.1177/00494755221130127.
https://doi.org/10.1177/0049475522113012... ^,88. Vento S, Guella L, Mirandola F, Cainelli F, Di Perri G, Solbiati M, et al. Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet. 1995;346(8975):608-609. doi: 10.1016/s0140-6736(95)91438-2.
https://doi.org/10.1016/s0140-6736(95)91... ^,99. Hong JK, Chopra S, Kahn JA, Kim B, Khemichian S. Autoimmune hepatitis triggered by COVID-19. Intern Med J. 2021;51(7):1182-1183. doi: 10.1111/imj.15420.
https://doi.org/10.1111/imj.15420... . However, information on dengue virus as a possible immune system trigger is limited, with only one case report associating dengue infection and AIH ⁷7. Jagtap AB, Chirant S, Chaitanya V, Lall B, Porwal YC. Autoimmune hepatitis unmasked by dengue infection - An unexplored and rare association. Trop Doct. 2023;53(1):181-182. doi: 10.1177/00494755221130127.
https://doi.org/10.1177/0049475522113012... .

Serology for dengue IgM infection may show false positives in certain patients, as has been reported in systemic lupus erythematosus and in vitro studies ¹⁵15. Kamolratanakul S, Thungthong P, Nakhakes C, Kittiyanpanya C, Chonsawat P, Chamnanchanunt S. False-positive dengue IgM test result in a patient with systemic lupus erythematosus: a case report. Asian Biomed. 2020;14(5):209-213. doi: 10.1515/abm-2020-0030.
https://doi.org/10.1515/abm-2020-0030... ^,1616. Takasaki T, Nawa M, Yamada KI, Harada M, Takeda A, Kurane I. Evaluation of dengue IgM detection tests using sera from patients with autoimmune diseases. J Virol Methods. 2002;102(1-2):61-66. doi: 10.1016/s0166-0934(01)00449-9.
https://doi.org/10.1016/s0166-0934(01)00... . One hypothesis is that this phenomenon may be due to cross-reactivity between the nonstructural (NS) protein that is specific to dengue virus and its interaction with host cells, or it could be due to the presence of rheumatoid factor antibodies, which can trigger nonspecific binding in the coating on IgM anti-human antibodies ¹⁶16. Takasaki T, Nawa M, Yamada KI, Harada M, Takeda A, Kurane I. Evaluation of dengue IgM detection tests using sera from patients with autoimmune diseases. J Virol Methods. 2002;102(1-2):61-66. doi: 10.1016/s0166-0934(01)00449-9.
https://doi.org/10.1016/s0166-0934(01)00... ^,1717. Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, et al. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology. 2020;72(2):671-722. doi: 10.1002/hep.31065.
https://doi.org/10.1002/hep.31065... . Our patient initially had nonspecific symptoms and mild elevation in liver function tests, which supported the finding of dengue virus as the primary infection that produced an activation of the immune system that subsequently triggered the onset of AIH, causing a further increase in liver function test values. Autoimmune tests were carried out due to the torpid clinical and laboratory course, revealing positive autoantibodies compatible with AIH in the patient. However, a liver biopsy to confirm the diagnosis was considered unfeasible due to gestation. The risk outweighed the benefits and there was a high probability for the diagnosis of AIH. A limitation of this case report was the absence of liver biopsy confirmation. However, the favorable response to corticosteroid therapy in our patient confirms the hypothesis that the presentation was attributable to an autoimmune response triggered by dengue virus infection, leading to acute liver failure. This occurrence is rare due to protective immunologic changes during pregnancy. Elevated estrogen and progesterone levels contribute to an increase in regulatory and Th2 T cells, involved in the anti-inflammatory pathway, while decreasing the expression of Th1 and Th17 cells, corresponding to the pro-inflammatory pathway ¹⁷17. Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, et al. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology. 2020;72(2):671-722. doi: 10.1002/hep.31065.
https://doi.org/10.1002/hep.31065... . Corticosteroid therapy was effective and the patient was successfully removed from the liver transplant list. During the postpartum period, azathioprine was introduced along with continuous prednisone therapy to maintain disease control, given the high risk of flares due to decreased hormone levels, which restore the proinflammatory state of Th1 and Th17 cells ¹⁸18. Braga A, Vasconcelos C, Braga J. Autoimmune hepatitis and pregnancy. Best Pract Res Clin Obstet Gynaecol. 2020;68:23-31. doi: 10.1016/j.bpobgyn.2020.03.007.
https://doi.org/10.1016/j.bpobgyn.2020.0... . Close monitoring during the first six months postpartum is crucial to identify disease flares ¹²12. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015;63(4):971-1004. doi: 10.1016/j.jhep.2015.06.030.
https://doi.org/10.1016/j.jhep.2015.06.0... ^,1717. Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, et al. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology. 2020;72(2):671-722. doi: 10.1002/hep.31065.
https://doi.org/10.1002/hep.31065... ^,1919. Wang CW, Grab J, Tana MM, Irani RA, Sarkar M. Outcomes of pregnancy in autoimmune hepatitis: A population-based study. Hepatology. 2022;75(1):5-12. doi: 10.1002/hep.32132.
https://doi.org/10.1002/hep.32132... .

The positive response to corticosteroid therapy confirmed our suspicion of AIH in a patient infected with dengue virus. It is crucial that patients who respond well initially to high-dose corticosteroids be considered for adjuvant therapy, such as azathioprine, while gradually reducing the corticosteroid dose to minimize side effects and maintain a good clinical and laboratory response ¹²12. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol. 2015;63(4):971-1004. doi: 10.1016/j.jhep.2015.06.030.
https://doi.org/10.1016/j.jhep.2015.06.0... ^,1717. Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, et al. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology. 2020;72(2):671-722. doi: 10.1002/hep.31065.
https://doi.org/10.1002/hep.31065... . Regular follow-up is essential for at least a couple of years after diagnosis to maintain disease control and prevent relapses ¹⁷17. Mack CL, Adams D, Assis DN, Kerkar N, Manns MP, Mayo MJ, et al. Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases. Hepatology. 2020;72(2):671-722. doi: 10.1002/hep.31065.
https://doi.org/10.1002/hep.31065... .

We present the first case of a pregnant woman with dengue virus infection who subsequently developed AIH, confirmed by clinical course, immunological markers and positive response to treatment with corticoids and azathioprine. It is important for regions with high prevalence of dengue infection and patients susceptible to autoimmune diseases to consider this as a potential differential diagnosis. The exact mechanism by which this virus triggers AIH in susceptible patients remains unclear and further studies are needed due to the high prevalence of mosquito-borne diseases worldwide.

References

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