To the Editor:
SARS-CoV-2 vaccines were rapidly developed and authorized for use. Two of three approved vaccines in the United States – Pfizer-BioNTech and Moderna – utilize mRNA technology deployed in human vaccines for the first time. Additionally, Johnson & Johnson developed a viral vector vaccine.
No instances of liver injury were reported in phase II/III trials.1 Cases of acute liver injury following SARS-CoV-2 vaccination have been reported2 , 3 – the injury pattern is usually hepatocellular, mimicking autoimmune hepatitis. No population-based studies investigating the risk and characteristics of liver injury following SARS-CoV-2 vaccination exist. We investigated the frequency and pattern of liver injury after SARS-CoV-2 vaccination across vaccine types, injury time course, and recovery using the Indiana University Health Enterprise Data Warehouse. Analysis was conducted following institutional review board (IRB) approval.
Our vaccine-exposed cohort included (a) patients receiving SARS-CoV-2 vaccination between December 2020 and October 2021 (3,546,047 patients) and (b) without pre-existing liver disease, defined as alanine aminotransferase (ALT) <45 U/L, aspartate aminotransferase (AST) <45 U/L, alkaline phosphatase (ALP) <150 U/L, and total bilirubin (TB) <1.2 mg/dl on 2 consecutive occasions with no ALT/AST >45 U/L, ALP >150 U/L, and TB >1.2 mg/dl within 24 months prior to the first SARS-CoV-2 vaccine dose (470,274 patients). For comparison, we identified a control group including patients receiving the influenza vaccine in 2019 at Indiana University Health and Eskenazi Health (130,067 patients) with no pre-existing liver disease (21,784 patients). Data collection ended on 10/29/2021.
Using published criteria for investigating drug-induced liver injury (DILI) in epidemiological studies,[4], [5], [6] we defined “liver injury after vaccination” as ALT >200 U/L and/or ALP >250 U/L and/or TB >2.5 mg/dl on at least 2 consecutive occasions within 12 weeks after the first or second vaccine dose, in the absence of positive hepatitis B virus surface antigen or hepatitis C virus antibody, alcohol consumption, exposure within 3 months to common DILI drugs (amoxicillin-clavulanate, isoniazid, diclofenac, nitrofurantoin, sulfamethoxazole/trimethoprim, minocycline, infliximab, azathioprine, ibuprofen, rifampin, pyrazinamide), heart failure (ICD-10 codes I50.xx, I11.0, I13.0, I97.13, I09.8), or hospitalization within previous 3 months. Qualifying labs were collected as part of routine clinical care. R-value was calculated using initial qualifying data to identify the pattern of liver injury.7 We compared liver injury frequencies after vaccine among SARS-CoV-2 (mRNA, viral-vector) and influenza vaccines.
Among 470,274 individuals in the vaccine-exposed cohort, 177 individuals (0.038%) met liver injury criteria after SARS-CoV-2 vaccination. Sixty percent were female, 90% White and average age at first vaccine was 70 years. The frequency of liver injury after vaccine was no different between mRNA and viral-vector vaccines (0.038% vs. 0.024%, p = 0.26). Liver injury was observed after the first dose in 14% and second dose in 86%. Average time to injury after the first dose was 29 ± 21 days and second was 45 ± 25 days. Liver injury pattern was hepatocellular in 45%, cholestatic in 35%, and mixed in 20%. Peak mean for AST, ALT, ALP and TB were 800 IU/L, 553 IU/L, 405 IU/L, and 3.1 mg/dl, respectively. 29% of patients ever had TB >2.5 mg/dl. Follow-up liver biochemistries were available in 42 patients with liver injury after vaccination and liver tests normalized in 48% of them (defined as serum ALT <45 U/L, ALP <250 U/L and TB <2.5 mg/dl). Mean duration between first abnormal to first normal TB was 8 ± 14 days. Compared to influenza control, SARS-CoV-2 vaccination was associated with a lower frequency of liver injury after vaccination (0.038% vs. 0.069%, p = 0.04) (Table 1 ).
Table 1.
Demographic and clinical data of individuals with liver injury after vaccination.
| Results, mean ± SD | All SARS-CoV-2 vaccines | Pfizer | Moderna | J&J | Influenza vaccine |
|---|---|---|---|---|---|
| Total vaccinated individuals, n | 3,546,047 | 2,062,837 | 1,230,887 | 252,323 | 130,067 |
| Vaccine-exposed cohort, n | 470,274 | 257,254 | 188,097 | 24,923 | 21,784 |
| Total individuals with liver injury, n | 177 | 87 | 84 | 6 | 15 |
| Individuals with liver injury, % | 0.038% | 0.034% | 0.045% | 0.024% | 0.069% |
| Age, years, mean ± SD | 70 ± 14 | 71 ± 14 | 70 ± 14 | 52 ± 16 | 56 ± 19 |
| Females (%) | 60 | 60 | 59.5 | n/a | 60 |
| Whites (%) | 90 | 88.5 | 92 | n/a | 80 |
| Liver injury after 1st dose, % | 14 | 9 | 12 | 100 | 100 |
| Time from 1st vaccine dose to 1st abnormal liver test | 29 ± 21 | 26 ± 24 | 24 ± 16 | 43 ± 19 | 12 ± 24 |
| Liver injury after 2nd dose, % | 86 | 91 | 88 | n.a. | n.a. |
| Time from 2nd vaccine dose to 1st abnormal liver test | 45 ± 25 | 46 ± 26 | 45 ± 24 | n.a. | n.a. |
| Baseline labs | |||||
| AST (U/L), mean ± SD | 20 ± 7 | 20 ± 6 | 21 ± 8 | 19 ± 6 | 21 ± 8 |
| ALT (U/L), mean ± SD | 18 ± 9 | 17 ± 8 | 18 ± 9 | 19 ± 7 | 23 ± 10 |
| ALP (U/L), mean ± SD | 83 ± 25 | 85 ± 25 | 81 ± 25 | 77 ± 21 | 78 ± 26 |
| TB (mg/dl), mean ± SD | .5 ± .22 | .51 ± .22 | .49 ± .23 | .45 ± .14 | .52 ± .23 |
| Pattern of liver injury | |||||
| R ≥5 (hepatocellular), % | 45 | 39 | 54 | 0 | n.a. |
| R <2 (cholestatic), % | 35 | 38 | 31 | 50 | n.a. |
| 2 ≤R < 5 (mixed), % | 20 | 23 | 15 | 50 | n.a. |
| Peak liver tests after vaccination | |||||
| AST (U/L), mean ± SD | 800 ± 1757 | 657 ± 1454 | 983 ± 2058 | 313 ±147 | 443 ± 731 |
| ALT (U/L), mean ± SD | 553 ± 721 | 477 ± 578 | 650 ± 855 | 313 ± 176 | 494 ± 626 |
| Alkaline phosphatase (U/L), mean ± SD | 405 ± 429 | 345 ± 266 | 465±1015 | 443 ± 477 | 251 ± 199 |
| Total bilirubin at peak (mg/dl), mean ± SD | 3.1 ± 4.2 | 3.3 ± 4.4 | 3 ± 4 | 2.8 ± 4 | 2.9 ± 2.2 |
| Cases ever with TB >2.5 mg/dl, % | 29 | 34 | 23 | 33 | 47 |
| Follow-up | |||||
| Cases with follow-up labs, n | 42 | 21 | 20 | 1 | n.a. |
| Cases with normalization, n | 20 | 10 | 10 | 0 | n.a. |
| Time to normalization from first abnormal to first normal lab value (days) | |||||
| AST | 43 ± 39 | 36 ± 30 | 49 ± 46 | n.a. | n.a. |
| ALT | 50 ± 35 | 42 ± 30 | 56 ± 40 | n.a. | n.a. |
| ALP | 30 ± 40 | 15±11 | 44 ± 47 | n.a. | n.a. |
| TB | 8 ± 14 | 7 ± 11 | 8 ± 16 | n.a. | n.a. |
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TB, total bilirubin. Frequencies of liver injury after vaccination compared using the Chi-Square test.
Liver injury after vaccination is a rare adverse effect that has been associated with other vaccines.8 , 9 A latency of injury of between 6 and 46 days after the first SARS-CoV-2 vaccine dose was reported in a case series which included individuals with baseline liver disease.3 We observed longer latency and most injury occurred after the second dose. This difference may be related to our exclusion of those with a history of liver disease or our cohort may be a more comprehensive sample. Underlying mechanisms remain unclear, but toll-like receptors 3, 7, and 8 have been hypothesized to contribute as they recognize RNA and have the potential to induce inflammatory responses. Modification of mRNA to limit innate and adaptive immune responses was key for vaccine development.10
Limitations include a retrospective approach, application of inclusion and exclusion criteria using electronic health record data, identification of liver injury after vaccine using surrogate biochemical criteria, and extrapolation to individuals with previously elevated liver biochemistries. We were unable to conduct manual chart review to adjudicate the liver injuries to determine the causal relationship between vaccine and liver injury.
Unexplained liver test abnormalities are seen in 0.038% individuals following SARS-CoV-19 vaccination – a lower frequency than following influenza vaccination. This study adds to the growing body of evidence demonstrating the safety of SARS-CoV-19 vaccines relative to other vaccines that are standard of care.
Financial support
There was no external funding for this study. Supported in part by K23 DK114561 to CL.
Authors’ contributions
JG: design, data interpretation, manuscript drafting. CL: design, data interpretation, and manuscript editing and preparation. ET: data collection NC: Study concept, design, data interpretation, and manuscript editing.
Data availability statement
Analytical methods and study material are described in the manuscript. Additional details can be obtained by contacting the corresponding author.
Conflict of interest
No relevant conflicts of interest to declare. Dr. Chalasani has paid consulting agreements with and research grants from several pharmaceutical companies, but they are not directly or significantly related to this epidemiological study.
Please refer to the accompanying ICMJE disclosure forms for further details.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jhep.2022.02.014.
Supplementary data
The following are the supplementary data to this article:
References
- 1.Polack F.P., Thomas S.J., Kitchin N., Absalon J., Gurtman A., Lockhart S., et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med. 2020;383:2603–2615. doi: 10.1056/NEJMoa2034577. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Bril F. Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: one or even several swallows do not make a summer. J Hepatol. 2021;75:1256–1257. doi: 10.1016/j.jhep.2021.08.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Shroff H., Satapathy S.K., Crawford J.M., Todd N.J., VanWagner L.B. Liver injury following SARS-CoV-2 vaccination: a multicenter case series. J Hepatol. 2021;76:211–214. doi: 10.1016/j.jhep.2021.07.024. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Chalasani N., Bonkovsky H.L., Fontana R., Lee W., Stolz A., Talwalkar J., et al. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology. 2015;148:1340–1352.e1347. doi: 10.1053/j.gastro.2015.03.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lammert C., Imler T., Teal E., Chalasani N. Patients with chronic liver disease suggestive of nonalcoholic fatty liver disease may be at higher risk for drug-induced liver injury. Clin Gastroenterol Hepatol. 2019;17:2814–2815. doi: 10.1016/j.cgh.2018.12.013. [DOI] [PubMed] [Google Scholar]
- 6.Aithal G.P., Watkins P.B., Andrade R.J., Larrey D., Molokhia M., Takikawa H., et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89:806–815. doi: 10.1038/clpt.2011.58. [DOI] [PubMed] [Google Scholar]
- 7.LiverTox . National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): 2012. Clinical and research information on drug-induced liver injury. [PubMed] [Google Scholar]
- 8.Sasaki T., Suzuki Y., Ishida K., Kakisaka K., Abe H., Sugai T., et al. Autoimmune hepatitis following influenza virus vaccination: two case reports. Medicine (Baltimore) 2018;97 doi: 10.1097/MD.0000000000011621. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.van Gemeren M.A., van Wijngaarden P., Doukas M., de Man R.A. Vaccine-related autoimmune hepatitis: the same disease as idiopathic autoimmune hepatitis? Two clinical reports and review. Scand J Gastroenterol. 2017;52:18–22. doi: 10.1080/00365521.2016.1224379. [DOI] [PubMed] [Google Scholar]
- 10.Stuart L.M. In gratitude for mRNA vaccines. N Engl J Med. 2021;385:1436–1438. doi: 10.1056/NEJMcibr2111445. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Analytical methods and study material are described in the manuscript. Additional details can be obtained by contacting the corresponding author.