Volume 5 Issue 4, November 2022, pp. 535-539

BACKGROUND: Widespread administration of COVID-19 vaccinations have led to reports of rare but potentially serious side effects. METHODS: We present two cases of acute hepatitis following mRNA BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccination. RESULTS: A 25-year-old male presented to hospital with progressive jaundice 5 days following his second dose of Comirnaty. Initial bloodwork revealed severe hepatocellular enzyme elevation and conjugated hyperbilirubinemia with preserved INR. Extensive serologic workup was negative, with normal imaging. Percutaneous liver biopsy was performed and revealed acute cholestatic hepatitis possibly related to drug-induced liver injury. He was started on prednisone 40 mg daily with good initial response but had a second flare; a biopsy was repeated which showed near-identical findings. Steroids were discontinued given non-response and the patient had gradual near complete resolution of liver enzymes and hyperbilirubinemia. A 32-year-old male presented with a 4-week history of nausea followed by progressive choluria, jaundice, and pruritis. He received his second dose of Comirnaty vaccination two weeks prior to presentation. Initial bloodwork showed mixed enzyme elevation with hyperbilirubinemia. Serological workup and imaging were unrevealing. He underwent liver biopsy which showed severe intrahepatic cholestasis, with drug-induced liver injury being suggested as most likely cause. His course was self-limited with resolution of serological abnormalities and symptoms. CONCLUSIONS: While overwhelmingly safe on a population level, our case series illustrate two cases of acute icteric hepatitis following mRNA BNT162b2 vaccination. Clinicians should be aware of this association with hepatic inflammation and consider vaccine history an important component of evaluating patients with acute liver injury.

The SARS-CoV-2 pandemic has resulted in millions of deaths globally. More recent efforts have shifted focus towards rapid development, testing and widespread administration of vaccinations to protect against COVID-19 infection. mRNA vaccine BNT162b2 (Comirnaty, Pfizer-BioNTech) has been shown in various laboratory and real-word settings to prevent serious illness and death from COVID-19 with a favourable safety profile (1). In a 6-month safety and efficacy trial, no serious liver-related events were reported the vaccination cohort (2).

We present two cases of acute hepatitis temporally related to Comirnaty vaccination.

Case 1

A 25-year-old man presented to hospital with a history of progressive jaundice 5 days following his second dose of Comirnaty vaccination. His medical history was significant for mild autism, and he took no medications. Upon presentation to hospital, index bloodwork revealed ALT 1902 U/L, ALP 163 U/L and total bilirubin 376 umol/L (direct 311 μmol/L), INR 1.1. Examination revealed jaundice but no features of chronic liver disease. Initial workup including hepatitis A/B/C, HIV, cytomegalovirus, Epstein-Barr virus, herpes simplex virus, ceruloplasmin, alpha-1-antitrypsin, immunoglobulins, anti-mitochondrial, anti-smooth muscle antibodies and antinuclear antibodies was negative. He had a low initial anti-nuclear antibody titre of 1:80, which was negative on repeat 1month later. An abdominal ultrasound and MR Abdomen revealed only gallbladder wall thickening felt related to adjacent hepatitis. Percutaneous liver biopsy was performed and revealed acute cholestatic hepatitis with parenchymal-centric, cytotoxic pattern of injury; this was consistent with non-specific drug-induced liver injury. While liver enzymes were declining, the bilirubin continued to increase; he was started on prednisone 40 mg daily with good ongoing declining ALT and dramatic fall in serum bilirubin. He then had an abrupt increase in ALT at which time steroids were discontinued. A biopsy was repeated shortly thereafter and revealed near-identical findings. Gradually, his hyperbilirubinemia improved but did not normalize entirely. He had a third flare of hepatocellular enzymes prompting a third biopsy which revealed progression of histological features with lymphocytic infiltrate and parenchymal loss and apoptotic bodies identified throughout (Figures 1 and 2). There was suggestion of emerging fibrosis. Biochemically, his enzymes would again begin to normalize. Figure 3 summarizes serum ALT, ALP, Bilirubin in relation to interventions described earlier.

Figure 1: Third percutaneous biopsy of Case 1; H & E stained section of liver biopsy at 100 x magnification showing parenchymal-centric, cytotoxic pattern of injury with lymphocytic infiltrate and significant parenchymal loss with apoptotic bodies consistent with acute hepatitis

Figure 2: Third percutaneous biopsy of Case 1; trichrome-stained section of liver biopsy at 100 x magnification showing significant parenchymal collapse but with emerging fibrosis

Figure 3: Liver enzyme and bilirubin trend over time in relation to liver biopsies and steroid therapy, Case 1

Case 2

A 32-year-old man, was referred to outpatient hepatology clinic with a 4-week history of nausea followed by progressive choluria, jaundice, and pruritis accompanied by 15 lbs weight loss. The onset of his symptoms occurred 2 weeks after his second Comirnaty vaccination. His medical history was significant for anxiety and previous cholecystectomy in 2014 for biliary colic. His medications included longstanding escitalopram and lorazepam as needed. Exposure history was entirely negative. Initial bloodwork revealed ALT 422 U/L, ALP 210 U/L, total bilirubin 65 μmol/L. Serological workup including hepatitis A/B/C, EBV, HIV, ceruloplasmin, α1-antitrypsin, immunoglobulins, anti-actin, and tissue-transglutaminase was negative. An ultrasound showed non-specific hyperechoic appearance of the periportal spaces in keeping with periportal edema resultant from acute hepatitis. He underwent liver biopsy which showed severe intrahepatic cholestasis with prominent rosette formation and cytoplasmatic degenerative changes, with drug-induced liver injury being suggested as most likely cause. His pruritis was treated with bilastine (Blexten) and later cholestyramine was added for additional relief. He had gradual resolution of his enzymes and hyperbilirubinemia with improvement in his symptoms (Figure 4).

Figure 4: Liver enzyme and bilirubin trend over time, Case 2

To our knowledge, these represent the first cases of severe icteric hepatitis, without autoimmune features following mRNA BNT162b2 vaccination. Bril et al first published a case of autoimmune hepatitis following first dose of BNT162b2 vaccination in a post-partum female (3). Following this, several reports of autoimmune hepatitis following other COVID-19 vaccinations including mRNA-1273 (Spikevax, Moderna) and ChAdOx1 nCoV-19 (Vaxzevria, Oxford-AstraZeneca), have been published, all after first-dose, with predominantly autoimmune pattern of injury, and featuring marked response to corticosteroid therapy (49). A single case of self-limited hepatitis following second dose of BNT162b2 published by Mann et al was relatively mild in severity and disease course limited to 1-week (13).

While both patients had features of acute hepatitis satisfying ‘Hy’s Law,’ their clinical course and presentation differed significantly (10). Patient 1 had a short latency period following vaccination, presenting non-specifically with nausea and having predominant hepatocellular elevation despite the cholestatic pattern of injury on biopsy. This was accompanied by minimal response to corticosteroids and a relapsing disease course. Conversely, Patient 2 had onset of illness several weeks following vaccination and experienced symptoms more typical of pure cholestasis with severe pruritis. This accompanied a sharp spike in hepatocellular enzymes which would resolve quickly and be followed by a longer period of cholestatic enzyme elevation. This patient would experience a relatively self-limited disease course requiring only symptomatic management of pruritis.

Similar to previously published cases of autoimmune and acute hepatitis following COVID-19 vaccination, causation cannot be definitively proven. However, unlike the predominant theory of molecular mimicry as a mechanistic trigger for autoimmune hepatitis, cholestatic drug-induced liver injury has been relatively well-established and accepted in the medical literature (11,12). Furthermore, unlike other case reports of autoimmune hepatitis, our patients presented after their second dose of vaccination, possibly suggesting immune exposure.

Overall, rapid deployment of vaccines against COVID-19 has undoubtedly provided immense benefit in the efforts in combatting the current SARS-CoV-2 pandemic. We hope that these cases will add to the emerging body of literature of rare, but potentially serious side-effects of these agents that practitioners should be mindful of as global vaccination efforts continue. Clinicians need to be aware that mRNA-based COVID-19 vaccination may be associated with severe and prolonged hepatic inflammation and a vaccine history is an important component of the evaluation of patients with acute liver injury.

Conceptualization, VG Bain; Data Curation, M Cheah; Resources, S Girgis; Writing – Original Draft, M Cheah; Writing – Review & Editing, M Cheah, S Girgis, VG Bain.

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We confirm that informed patient consent or consent of the parents or guardians of minors has been secured from all patients whose personal information is included in the manuscript.

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No funding was received for this work.

The authors have nothing to disclose.

This manuscript has been peer reviewed.

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