9 case reports of autoimmune hepatitis following COVID-19 vaccination

A 65-year-old woman experienced mild abdominal pain shortly after receiving the first dose of Moderna-COVID-19 vaccine.

She tested negative for hepatitis A virus, human immunodeficiency virus, cytomegalovirus, Epstein-Barr virus and herpes simplex virus type 1 and 2, as well as hepatitis B, C and E viruses. Her blood tests and thyroid function were normal, except elevated ALT/AST and positive antinuclear antibody. 

Five weeks after vaccination, the patient presented with jaundice and choluria. Liver profile was worsening, and IgG levels were now elevated.  Percutaneous liver biopsy was performed, revealing a marked expansion of the portal tracts due to dense inflammatory infiltrate, with aggregates of plasma cells; The score of simplified diagnostic criteria of the International Autoimmune Hepatitis Group was 8, indicative of autoimmune hepatitis (AIH). Treatment with prednisolone 60 mg/day was started with a quick improvement of liver function tests and normalization of IgG levels. One month after initial diagnosis, the patient remains well on a tapering course of corticosteroids.  

Antibodies against the spike protein S1 of SARS-CoV-2 had a high affinity against some human tissue proteins. As vaccine mRNA codes the same viral protein, they can trigger autoimmune diseases in predisposed patients.

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A 79-year-old man came to the emergency room in September 2021 with a 3-month history of right upper quadrant abdominal pain associated with jaundice, pruritus, acholia, and choluria. He received the ChAdOx1 nCoV-19 vaccine (AZD1222) on May 9th, 2021, developing the above-mentioned symptomatology 15 days after the first dose. Despite clinical manifestations, he received the second dose on August 5, 2021 

Examination revealed conjunctival and soft palate jaundice as well as generalized yellow pigmentation of the skin, and mild abdominal tenderness in the right upper quadrant without other significant findings. Blood tests showed mixed hyperbilirubinemia (11.9 mg/dL) with direct bilirubin predominance (9.39 mg/dL), elevated transaminases (GOT 2003 U/L, GPT 1994 U/L), negative hepatotropic viruses’ profile (i.e., hepatitis A, B, C, and E), and non-reactive IgG and IgM serology for cytomegalovirus and Epstein-Barr. In addition, the patient had mild lymphopenia (0.910 10x^3/μL), with normal leukocyte (5.06 10x^3/μL) and platelet counts (253 10x^3/μL). Fibrinogen, erythrocyte sedimentation rate (ESR), and C reactive protein were within the normal range. Abdominal ultrasound showed edema of the gallbladder walls with a pattern described in acute hepatitis without cholelithiasis. The spleen was normal in size and shape, despite a venous doppler showing increased portal diameter and elevated portal flow velocity (15 mm and 22 cm/s, respectively). The upper gastrointestinal endoscopy showed esophagitis (Forrest III) and chronic antral gastritis. In addition, cholangioresonance showed no biliary obstruction nor additional relevant findings.Liver biopsy, performed on September 20th (after discharge and initiation of immunomodulatory management), showed focal cholestasis and lobulation of the parenchyma, marked ductular proliferation, as well as lymphocytic infiltrate in the portal spaces with the presence of eosinophils, corresponding to a necroinflammatory hepatitis grade 2 stage 2 with focal cholestasis. Altogether, the data indicate fulfillment of the International Autoimmune Hepatitis Group (IAIHG) criteria for type 1 AIH and suggest that it was developed after COVID-19 vaccination, meeting most of the Bradford Hill causality criteria.

Therapy with hydrocortisone (100mg per day for 3 days) was initiated, switched to prednisone (50mg per day). Azathioprine (50mg per day) was initiated. During the nine days following the establishment of treatment, the patient presented a progressive decrease in the level of liver enzymes. In a follow-up consultation one moth later, the patient's clinical condition continued to improve, as did his liver enzyme

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A 63-year-old male without a history of autoimmune diseases presented to his general practictioner with jaundice, fatigue and loss of appetite starting seven days after the first dose of the mRNA-1273 SARS-CoV-2 vaccine.  The patient responded well to prednisone treatment over two weeks. He was diagnosed with autoimmune hepatitis (AIH).  Only long-term follow up will allow to establish if this hepatitis behaves as AIH or as AIH-like drug-induced liver injury.

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A previously healthy 47-year-old Caucasian man received his 1st Moderna vaccine dose on the 26 April 2021. He noted malaise and jaundice 3 days after. Investigations on the 30th April showed elevated serum bilirubin and liver function tests (LFT): alanine aminotransferase (ALT), alkaline phosphatase (ALP), albumin. Serum IgG was raised at 25.1 g/L (normal 6-16), IgM 2.2 g/L (0.5-2) and serum was positive for anti-nuclear antibody. Serological tests for HAV, HBV, HCV, HEV, EBV and CMV were negative and other blood tests were also normal. His jaundice faded and LFTs improved: bilirubin falling on 25th June to 69 μmol/L and ALT to 332 U/L. The patient received his 2nd Moderna vaccine dose on the 6 July 2021 (despite reporting the jaundice to the vaccination center) and the jaundice returned a few days after. Blood tests on 20th July found significantly elevated bilirubin 355 μmol/L, significantly elevated ALT 1,084 U/L and a raised prothrombin time (PT) of 18.4 seconds. After liver biopsy on the 21st July 2021, prednisolone 40 mg/day was commenced. Review of the liver biopsy showed acute active hepatitis: widespread areas of bridging necrosis, marked interface hepatitis, lymphoplasmatic inflammation including eosinophils, ballooned hepatocytes, multi-nucleated giant cells, and emperipolesis. He was discharged on prednisolone and on follow-up, blood tests continue to improve, and PT normalized within 2 weeks.

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A 61-year-old woman presented with malaise, fatigue, loss of appetite, nausea and yellow eyes. She had a Pfizer/BioNTech BNT162b2 mRNA vaccine a month ago. Her physical examination revealed jaundice all over the body, especially in the sclera. The liver biopsy revealed histopathological findings consistent with autoimmune hepatitis (AIH). She rapidly responded to steroid therapy.

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6th case added from an April 20, 2022 publication:

The 52-year-old male patient with no remarkable medical history other than pre-existing hypothyroidism under long-term substitution therapy with levothyroxine and normal historic liver function tests (LFT) developed progressive nausea, fatigue, loss of appetite and pruritus with symptoms starting approximately 10 days after the first (prime) dose of the BNT162b2 mRNA vaccine. He subsequently developed jaundice and presented at his primary care physician with LFT indicative of acute mixed hepatocellular/cholestatic hepatitis (ALT: 2130 U/l, AP: 142 U/l gamma-GT: 217 U/l, Bilirubin 7.7 mg/dl) (Fig. 1). The patient was admitted to a primary care center 25 days post first vaccination. Viral hepatitis A, B, C and E as well as cytomegalovirus- and Epstein-Barr virus-infections were excluded by serology and/or PCR testing. HFE genotyping did not reveal hemochromatosis associated variations. There was also no significant alcohol consumption and autoimmune serology remained inconclusive with borderline AMA-M2 reactivity. The patient recovered rapidly without specific therapy and was discharged with decreasing LFTs after three days under leading differential diagnosis of a toxic hepatitis. Over the next two weeks, liver enzymes declined further, with normalization of AST and AP and the patient received his second (boost) dose of the BNT162b2 mRNA vaccine 41 days after the first vaccination. 20 days post boost vaccination (dpb), the patient re-experienced nausea and fatigue. Lab testing revealed a relapse of acute mixed hepatitis with (ALT 1939 U/l, ALP 167 U/l, bilirubin 2.9 mg/dl). He was subsequently referred to our tertiary center at 26dpb. Autoimmune serology was repeated with mild Hyperglobulinemia (IgG levels 1.02-fold of ULN, normal IgA and IgM levels), ANA (1:200) and borderline positivity for anti-smooth muscle antibodies and AMA-M2 while tests for anti-LKM remained negative. 

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7th case added from an October 2022 case report:  

A female patient in her late 20s presented to the hospital with yellowish discoloration of eyes, urine and stools 10 days after the first dose of Astrazeneca COVID-19vaccine. She had a history of asymptomatic COVID-19 infection 3 months ago and a history of chronic analgesic consumption for migraine. She was diagnosed as having AIH through extensive clinical and laboratory workup. 


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A 54-year-old woman received two doses of the Pfizer-BioNTech COVID-19 mRNA vaccine and an additional dose of the Moderna COVID-19 mRNA vaccine. Seven days after the third dose, she noticed fatigue, appetite loss and dark urine. Laboratory tests were consistent with severe liver injury and jaundice. Anti-smooth muscle antibody and HLA-DR4 were positive. Percutaneous liver biopsy showed pan-lobular inflammation with moderate infiltration of lymphocytes and macrophages, interface hepatitis, and rosette formation, confirming the diagnosis of autoimmune hepatitis (AIH). Dozens of cases of AIH after COVID-19 vaccination have been reported. Corticosteroids were effective in most cases, but some patients have died from liver failure after vaccination. This case illustrated the efficacy of azathioprine for steroid-refractory AIH induced by COVID-19

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9th case added in June 2023:

A 27-year-old man developed autoimmune-like hepatitis after the first dose of the BNT162b2 (mRNA) COVID-19 vaccine. He presented with sweating, febrile sensations, and general weakness. He did not have any medical histories. Although he was treated with biphenyl dimethyl dicarboxylate and ursodeoxycholic acid, the elevated liver enzyme levels persisted for 2 months. Liver biopsy demonstrated portal inflammation with rosette formation, interface hepatitis, and infiltration of lymphocytes, histiocytes, plasma cells, and eosinophils. Especially, centrilobular edema and necrosis were found. The symptoms and liver enzymes improved with prednisolone treatment. 


REFERENCE

Garrido I, Lopes S, Simões MS, Liberal R, Lopes J, Carneiro F, Macedo G. Autoimmune hepatitis after COVID-19 vaccine–more than a coincidence. Journal of autoimmunity. 2021 Dec 1;125:102741.

Camacho-Domínguez L, Rodríguez Y, Polo F, Gutierrez JC, Zapata E, Rojas M, Anaya JM. COVID-19 vaccine and autoimmunity. A new case of autoimmune hepatitis and review of the literature. Journal of translational autoimmunity. 2022 Jan 4:100140.

Ghielmetti M, Schaufelberger HD, Mieli-Vergani G, Cerny A, Dayer E, Vergani D, Beretta-Piccoli BT. Acute autoimmune-like hepatitis with atypical anti-mitochondrial antibody after mRNA COVID-19 vaccination: A novel clinical entity?. Journal of Autoimmunity. 2021 Sep 1;123:102706.

Tun GS, Gleeson D, Al-Joudeh A, Dube A. Immune-mediated hepatitis with the Moderna vaccine, no longer a coincidence but confirmed. Journal of Hepatology. 2021 Oct 5.

Avci E, Abasiyanik F. Autoimmune hepatitis after SARS-CoV-2 vaccine: New-onset or flare-up?. Journal of autoimmunity. 2021 Dec 1;125:102745.

Boettler T, Csernalabics B, Salié H, Luxenburger H, Wischer L, Alizei ES, Zoldan K, Krimmel L, Bronsert P, Schwabenland M, Prinz M. SARS-CoV-2 vaccination can elicit a CD8 T-cell dominant hepatitis. Journal of Hepatology. 2022 Apr 21.

Mathew M, John SB, Sebastian J, Ravi MD. COVID-19 vaccine triggered autoimmune hepatitis: case report. Eur J Hosp Pharm. 2022 Oct 7:ejhpharm-2022-003485. doi: 10.1136/ejhpharm-2022-003485. Epub ahead of print. PMID: 36207131.

Ueno M, Takabatake H, Itakura J, Fujita R, Kayahara T, Morimoto Y, Notohara K, Mizuno M. Corticosteroid-refractory autoimmune hepatitis after COVID-19 vaccination: a case report and literature review. Clin J Gastroenterol. 2023 Apr 7. doi: 10.1007/s12328-023-01794-x. Epub ahead of print. PMID: 37029249.

Kim JH, Chae HB, Woo S, Song MS, Kim HJ, Woo CG. Clinicopathological Characteristics of Autoimmune-Like Hepatitis Induced by COVID-19 mRNA Vaccine (Pfizer-BioNTech, BNT162b2): A Case Report and Literature Review. Int J Surg Pathol. 2023 Jun 4:10668969231177877. doi: 10.1177/10668969231177877. Epub ahead of print. PMID: 37272061.

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