Liver injury following SARS-CoV-2 vaccination: A multicenter case series

Authors: Hersh Shroff,1,∗Sanjaya K. Satapathy,2James M. Crawford,3Nancy J. Todd,4 and Lisa B. VanWagner1 J Hepatol. 2022 Jan  10.1016/j.jhep.2021.07.024 PMCID: PMC8324396PMID:  34339763

In response to the COVID-19 pandemic, two novel mRNA-based vaccinations against the SARS-CoV-2 virus have been manufactured and distributed in an unprecedented fashion. In light of their rapid uptake, providers must remain vigilant in their monitoring of new adverse events. In early 2021, multiple providers, communicating on AST LICOP and AASLD online forums, shared strikingly similar experiences with patients who presented with liver injury following COVID-19 vaccination with no other clear precipitants. Given the pattern, we report herein on a multicenter cohort of patients with liver injury following COVID-19 vaccination. No personally identifiable information or protected health information was collected for any patient. The series was reviewed by the Northwestern University IRB and deemed not to be human subjects research.

Our cohort includes 16 total patients (Table 1 ) aged 25 to 74, who presented between 5 to 46 days following their first vaccine dose (Pfizer: 12, Moderna: 4). Notably, 75% of patients (12/16) presented after their second vaccine dose.

Table 1

Patient characteristics.

CaseAge, sexLiver disease historyTiming of presentation (days)aPattern of injuryPeak lab valuesRelevant work-up (medications, labs, imaging)Biopsy findingscTreatmentRecovery status
ALT (U/L)ALP (U/L)Bili (mg/dl)INR (ratio)Inflammation severityd, locationCellular pattern of inflammationCholestasisd and bile duct featuresFibrosis
Pfizer vaccine
146, MNAFLD, prior
DILI (due to amoxicillin)
10Hep5941973.91.3ASMA 1:40
Other autoimmune and viral serologies negative
ERCP with new severe sclerosing cholangitis
+
Portal
No interface hepatitis
Mixed infiltrate+
Mild ductular proliferation
Focal portal and peri-portalEndoscopic biliary dilationRecovering
261, FNone34Hep2,3311603.71.3Received nitrofurantoin 3 months prior
ASMA 1:160, other autoimmune and viral serologies negative
+
Portal and lobular
No interface hepatitis
Lymphocytes and plasma cellsNone
Normal bile ducts
NoneOral prednisoneRecovering
361, MNone31Hep7652302.61.2Ibuprofen x 3 days
Autoimmune and viral serologies negative
+
Portal and lobular
No interface hepatitis
LymphocytesNone
Normal bile ducts
NoneNoneFully recovered
471, MHCV (treated);
Compensated cirrhosis
27Chol1013671.7UnkNone performedNo biopsy performedNoneRecovering
574, FExtramedullary hematopoiesis of unknown significance on prior liver biopsy27Hep1,7793911.11.0ANA 1:640, other autoimmune serologies negative
Viral serologies negative
No biopsy performedNoneFully recovered
673, MAIH (treated)b6Hep8131140.7UnkNone performedNo biopsy performedOral prednisoneRecovering
725, FNone24Hep6354652.81.0Ibuprofen x 2 days
ANA 1:640, ASMA 1:20; viral studies negative
No biopsy performedNoneRecovering
861, FNone42Hep1,7352871.51.1ANA 1:320, other autoimmune serologies negative
EBV viral load 78, VZV IgM+/IgG+
Hepatic steatosis on imaging
++/+++
Portal
No interface hepatitis
Mixed infiltrateNone
Neutrophilic peri-cholangitis
NoneOral prednisoneRecovering
937, FNone29Hep>5,0001442.85.5Autoimmune and viral serologies negativeNo biopsy performedNAC infusionFully recovered
1033, FAIH (treated)b
Compensated cirrhosis
28Hep173462.11.1None+/++
Portal and lobular with interface hepatitis
Lymphocytes and plasma cellsNone
Normal bile ducts
CirrhosisOral prednisoneFully recovered
1168, MAIH (treated)b
Compensated cirrhosis
19Hep245550.91.1Imaging with new diagnosis of solitary HCC++
Portal and lobular with interface hepatitis
Mixed with plasma cellsNone
Normal bile ducts
CirrhosisOral prednisoneRecovering
1270, FPrior biliary stricture after cholecystectomy41Mixed961400.5UnkNoneNo biopsy performedNoneRecovering
Moderna vaccine
1366, FAIH (treated)b5Hep1,1993525.91.1Received shingles vaccine 3 months earlier
Viral serologies negative
+++
Portal and lobular with interface hepatitis and central perivenulitis
Plasma cellsNone
Normal bile ducts
NoneOral prednisoneRecovering
1468, FNone15Hep2,367176252.2Autoimmune and viral serologies negative
E. Coli UTI treated with ceftriaxone (after ALI onset)
+++
Portal and lobular
Interface hepatitis not reported
UnknownNone
Severe bile ductular reaction
NoneIV steroids,
NAC infusion
Recovering
1559, FNone31Hep86936714.72.4Tylenol several days per week for preceding year
ANA 1:640, IgG 1,750 other autoimmune serologies negative
EBV VCA IgM+, IgG+
Other viral markers negative
+++
Portal and lobular
No interface hepatitis
LymphocytesNone
Ductular reaction
NoneIV steroidsRecovering
1665, MNone46Mixed2,6642,52222.31.2Taking Tylenol/Norco for 4 days prior to presentation due to recent knee surgery
ANA 1:1,240, ASMA 1:40, IgG normal
Viral serologies negative
+
Portal
No interface hepatitis
Lymphocytes+++
Occasional bile duct injury
NoneNoneRecovering

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AIH, autoimmune hepatitis; ALI, acute liver injury; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANA, anti-nuclear antibodies; ASMA, anti-smooth muscle antibodies; Bili, bilirubin; DILI, drug-induced liver injury; EBV, Epstein-Barr virus; HCC, hepatocellular carcinoma; INR, international normalized ratio; NAC, N-acetylcysteine; NAFLD, non-alcoholic fatty liver disease; UTI, urinary tract infection; VCA, viral capsid antigen.aIn relation to first dose of vaccine.bNo medication changes for over 6 months with normal preceding labs.cBiopsy findings are reported based on each institution’s written report. Biopsies were not independently reviewed.dSeverity of inflammatory infiltrate and cholestasis graded as follows: +, minimal or mild; ++, moderate; +++, severe/extensive.

Six patients had a history of chronic liver disease, including 4 (#6, 10, 11, 13) with autoimmune hepatitis (AIH) in treated remission (i.e., no medication changes or abnormal labs for a minimum of 6 months). Three patients had cirrhosis: 2 patients with AIH (#10 and 11) and 1 with previously treated HCV (#4).

The majority (13/16) of cases demonstrated a hepatocellular pattern of liver injury (peak alanine aminotransferase: 96 to >5,000 U/L). Of the remaining 3 cases, 1 (#4) was cholestatic and 2 (#12, 16) were mixed. Acute liver injury (ALI, defined as international normalized ratio [INR] >1.5) occurred in 3 patients (#9, 14, and 15; INR range 2.2 to 5.5); no patients developed acute liver failure.

Patient #1 was diagnosed with “new” sclerosing cholangitis via endoscopic retrograde cholangiopancreatography on this presentation; however, on chart review, he presented with drug-induced liver injury (DILI) (amoxicillin) two years earlier, at which time a magnetic resonance cholangiopancreatography showed subtle non-diagnostic biliary findings, raising the possibility of undiagnosed primary sclerosing cholangitis. At the time of presentation, the DILI was long-since resolved, and the current presentation appears to represent an ALI event in a patient with pre-existing cholangitis. Patient #2 had been prescribed a 3-day course of nitrofurantoin approximately 90 days prior to presentation. The scenario was deemed atypical for nitrofurantoin toxicity (particularly the short exposure and clinical presentation). Patients #3 and #7 used ibuprofen immediately following the second vaccine dose (2 to 3 days total, unknown total doses); patient #15 reported chronic acetaminophen use (3-4 grams for several days per week over the preceding year); and patient #16 had knee surgery 3 days prior to presentation and used alternating acetaminophen and acetaminophen-hydrocodone for a total of 4 days. None of these were deemed likely to be causative given the time frame and short exposures. No patient displayed laboratory evidence of viral hepatitis, and all patients tested negative for COVID-19 infection. While 7 of the 12 patients without previously known AIH had at least 1 positive autoimmune marker at the time of presentation, only 1 (#15) met IAIHG simplified criteria for “probable” AIH (anti-nuclear antibody 1:640, elevated IgG to 1,750 mg/dl, and biopsy “compatible” with AIH).1

Out of 16 patients, 10 underwent liver biopsy (Table 1). All exhibited portal inflammation (60% graded as moderate or severe). Five cases demonstrated a significant plasma cell component (of whom #10, 11, and 13 had pre-existing AIH and displayed interface activity), all of whom received prednisone. Cholestasis and bile duct reaction, though variably present, were only prominent in 1 case (#16) with severe cholestasis and minimal inflammation. Excluding patients with known cirrhosis (n = 3), significant fibrosis was not seen in any patient.

Out of 16 patients, 10 required hospitalization. In total, 6 of 16 patients required no treatment. Of the 10 who received treatment, 2 (#9, 14; both with ALI) received N-acetylcysteine infusions, and 8 (see Table 1) received steroids. Patient #1, newly diagnosed with sclerosing cholangitis, underwent biliary dilatation. Importantly, all patients recovered or were recovering from the acute event at the time of assembling our cohort.

We acknowledge that our series of patients with hepatic injury following mRNA-based COVID-19 vaccination contains retrospective and observational data without adjudication. Thus, our report is not structured to evaluate potential causality. In our patients with prior drug exposure (amoxicillin; nitrofurantoin; non-steroidal anti-inflammatory drugs, acetaminophen), the exposures were either too short or the presentations highly atypical (by laboratory data or histopathology) to be attributed solely to the medication. Thus, DILI is not readily implicated in this patient series, although it cannot be wholly excluded. We also consider unlikely direct hepatotoxicity from SARS-CoV-2 mRNA vaccines, noting the strong safety profile for delivery of lipid nanoparticle mRNA vaccines to human tissues.2 Rather, vaccine-induced immune-mediated hepatitis is a known phenomenon,3 , 4 and other autoimmune events (e.g., AIH, ITP) have been reported following COVID-19 vaccination.5 , 6 It is plausible that a similar mechanism is occurring here, whereby the host immune response directed against the COVID-19 spike protein triggers an aberrant, autoimmune-like hepatic condition in predisposed individuals. Many questions still remain. In particular, should patients at higher risk of hepatic autoimmunity (e.g., existing AIH, post-liver transplant) undergo pre-emptive laboratory monitoring post-vaccination? Will there be safety concerns for these patients if booster doses are recommended in the future?

We emphasize that our intent is not to promote vaccine hesitancy. The overwhelming benefits of these and other highly efficacious vaccines in the setting of a global pandemic greatly surpass any potential risk of liver injury that may exist. We simply aim to share a clinical scenario that has been observed independently by multiple providers at various institutions, with the hope that as vaccine uptake continues to increase, our shared experience can help in early recognition, further study, and management of potential adverse events.Go to:

Financial support

L.V.W. is supported by the National Heart, Lung and Blood Institute grant K23HL136891.Go to:

Authors’ contributions

Hersh Shroff (conceptualization, methodology, visualization, writing original draft, writing review and editing). Sanjaya K. Satapathy (visualization, resources, writing review and editing). James M. Crawford (visualization, resources, writing review and editing). Nancy J. Todd (resources, writing review and editing). Lisa B. VanWagner (conceptualization, methodology, resources, supervision, visualization, writing review and editing).Go to:

Data availability statement

Data and study materials will not be made available to other researchers.Go to:

Conflict of interest

The authors disclose no conflicts of interest.

Please refer to the accompanying ICMJE disclosure forms for further details.Go to:

Acknowledgements

We acknowledge the following individuals for assistance in contributing cases and reviewing the manuscript: Juan Pablo Arab (Pontificia Universidad Católica de Chile); Timea Csak (Northwell Health), Winston Dunn and Beth Floyd (University of Kansas); R. Todd Frederick (California Pacific Medical Center); Alexander Lemmer (Piedmont Healthcare); Benedict Maliakkal (Ascension Medical Group); Atoosa Rabiee (Washington DC VA Medical Center); and Priyanka Singh (Northwell Health).Go to:

Footnotes

Author names in bold designate shared co-first authorship

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhep.2021.07.024.Go to:

Supplementary data

The following is the supplementary data to this article:Multimedia component 1:Click here to view.(1.4M, pdf)Go to:

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