Liver injury after COVID-19 vaccination: Current status and future perspectives

Table 1 Case series focused on new-onset autoimmune hepatitis associated with coronavirus disease 2019 vaccination, n (%)/median (range)

Ref.	n	Demographics: Age, M/F	Pre-exisiting other autoimmune disorders	Pre-exisiting liver diseases	COVID-19 survivor	Vaccine	Injury after 1st/2nd/3rd/4th dose (%)	Pattern of injury (hep/chol/mixed) (%)	The median (range) time from last vacine dose to onset of liver injury (days)
[28]	53	> 11, 13/40	1 (1.9)	3 (6)	NA	mRNA: 48 (91); vector: 5 (9)	32/53/1.9/NA1	NA	8-142
[29]	12	62 (32-80), 6/6	6 (50)	NA	NA	mRNA: 9 (75); vector: 3 (25)	NA	NA	1st: 483; 2nd: 103
[30]4	6	> 39, 0/6	1 (17)	LC: 1 (17); PBC: 1 (17)	NA	mRNA: 6 (100)	33/33/17/17	NA	25 (6-40)
[31]	5	62 (47-72), 1/4	3 (60)	05	NA	mRNA: 3 (60); vector: 2 (40)	40/60/NA/NA	NA	14 (4-46)

¹Information was unavailable for 13% of cases.

²More than 72% of cases had onset within 30 days.

³Median duration (range) calculated from the date of vaccination to the diagnosis of liver injury.

⁴Among 76 individuals who developed acute autoimmune hepatitis following at least one coronavirus disease-19 vaccine dose, six cases occurring within 42 days post-vaccination, with detailed clinical data and a presumed higher likelihood of causal association, were used for analysis.

⁵One case was under evaluation for mild hypertransaminasemia; diagnosis was pending at the time of vaccination.

M: Male; F: Female; AIH: Autoimmune hepatitis; Chol: Cholestatic injury; COVID-19: Coronavirus disease 2019; Hep: Hepatocellular injury; LC: Liver cirrhosis; Mixed: Mixed injury; NA: Not applicable or not available; PBC: Primary biliary cholangitis.

Table 2 Case series focused on new-onset autoimmune hepatitis associated with coronavirus disease 2019 vaccination, n (%)

Ref.	Clinical presentation	Autoimmune liver disease-related data	Pathology, and/or diagnostic criteria	Therapy	Outcome at the end of follow-up	Rechallenge
[28]	Death: 1 (1.9); life-threatening: 10 (19); hospitalization: 18 (34); ER visit: 14 (26)	NA	NA	NA	Death: 1 (1.9)	NA
[29]	Transaminase > 20 × ULN: 10 (83); jaundice: 8 (67)	ANA+: 6 (50); ASMA+: 1 (8.3); ALKM+: 1 (8.3); median IgG: 1.2 XULN	Histology: n not available: Typical AIH: 8; compatible AIH: 3	IS: n not available	CBR to IS: 58%	NA
[30]1	Symptomatic: 5 (83); asymptomatic: 1 (17)	ANA+: 3 (50); ASMA+: 5 (83); AMA+: 2 (33); Anti-SLA+: 1 (17); elevated IgG: 6 (100)	n = 4 for liver biopsy: Fibrosis: 2 (50) including METAVIR score: 3	Steroid: 3 (50); steroid/azathioprine: 3 (50)	Long-term IS: 3 (50); lost to follow-up: 2 (33); Remission: 1 (17)	NA
[31]	No acute liver failure; one severe acute hepatitis with marked icterus	ANA+: 5 (100); IgG > 1600 mg/dL: 5 (100), HLA-DRB1 (*03:01: 3, *07:01: 2, *11:04: 1, *04: 1, *04:03: 1, *01:03: 1)3	n = 4 for liver biopsy: Simplified IAIHG criteria for the Dx of AIH2: 7-8, CIOMS–RUCAM score2 related to vaccine: 2 (20), 3 (60), 6 (20)	n = 4: Steroid/azathioprine: 3 (75); steroid: 1 (25)	Spontaneous regression: 1 (20); biochemical response to IS: 4 (80)	n = 4 (total 6 additional doses) same: 33; same platform: 13; different platform: 23; no relapse in transaminases

¹Among 76 individuals who developed acute autoimmune hepatitis following at least one coronavirus disease 2019 vaccine dose, six cases occurring within 42 days post-vaccination, with detailed clinical data and a presumed higher likelihood of causal association, were used for analysis.

²Assumed to be applied in the absence of direct citation.

³Data are presented as n.

AIH: Autoimmune hepatitis; ANA: Antinuclear antibody; AMA: Anti-mitochondrial antibody; ALKM: Anti–liver-kidney microsomal antibody; ASMA: Anti-smooth muscle antibody; CBR: Complete biochemical response; CIOMS–RUCAM: Council for International Organizations of Medical Sciences–Roussel Uclaf Causality Assessment Method; COVID-19: Coronavirus disease 2019; Dx: Diagnosis; ER: Emergency room; HLA: Human leukocyte antigen; IAIHG: International Autoimmune Hepatitis Group; IgG: Immunoglobulin G; IS: Immunosuppressants; NA: Not available; SLA: Soluble liver antigen; ULN: Upper limit of normal.

Table 3 Case reports of specific liver injury associated with coronavirus disease 2019 vaccination

Ref.	Age/sex	Pre-existing diseases	Vaccine	Injury after 1st/2nd/3rd/4th dose	Pattern of injury (hep/chol/mixed)1	Autoantibodies/viral markers2	Liver pathological findings	Diagnosis	Complications	Therapy	Outcome
[45]	33/male	Type I DM	mRNA	2nd	Hep	Negative	NA	Immune-related liver dysfunction	Glycemic excursion and Raynaud’s phenomenon	Increased insulin dose	Improvement of glucose level and liver function at 4 weeks after vaccination
[46]	80/female	IgG4-RD and resected left kidney cancer	NA	1st	NA	Negative	Infiltration of IgG-4+ cells and elevated IgG4+/CD38+ cell ratio	IgG4-related hepatopathy	Multiple lymphadenopathy	None	Spontaneous regression with no recurrence
[47]3	46/male	FL, HC, GB polyps	mRNA	1st	Mixed	Negative	NA	Vaccine-related and/or thyrotoxicosis-associated liver injury	Subacute thyroiditis	Steroid	Improvement 4 weeks after liver injury diagnosis except γGTP
[48]	40/male	None	Vector	NA	NA	NA/Negative	NA	Live injury due to secondary HLH	Secondary HLH	Steroid	Improvement of liver function
[49]	21/male	None	mRNA	2nd	NA	Negative/HBsAb+: IgG-HBcAb+	NA	Live injury due to secondary HLH	Secondary HLH	Steroid	Improved to normal laboratory values
[50]	65/male	CLL, RA	NA	1st	Hep	RF/negative	NA	Live injury due to secondary HLH	Secondary HLH	Steroid, etoposide	Rapid clinical improvement including liver function but death due to neutropenia and pneumonia
[51]	33/male	HL, allergies	mRNA	2nd	NA	NA/negative	Significant hepatic inflammation	Acute liver failure due to secondary HLH	Secondary HLH	Steroid, etoposide	Multiorgan failure
[52]	24/female	None	mRNA	1st	NA	ANA+/negative4	NA	Live injury due to secondary HLH	Secondary HLH	IVIG, steroid, anakinra	Abdominal laboratory findings gradually resolved
[53]	14/female	None	mRNA	1st	NA	NA/EBV DNA+	NA	Live injury due to secondary HLH	Secondary HLH due to vaccine and EBV infection	IVIG, VA-ECMO, steroid	Hemogram and inflammatory markers normalized gradually
[54]	68/female	NA	Vector	1st	NA	NA/Negative	NA	Live injury due to secondary HLH	Secondary HLH	antibiotics	NA regarding liver injury but improved HLH
[55]	43/female	Chronic EBV infection	Inactivated	1st	NA	ANA-/EBV DNA+	NA	Live injury due to secondary HLH	Secondary HLH due to vaccine on chronic EBV infection	Steroid	Abdominal laboratory abnormalities improved gradually

¹Classification based on Ref. 35, although not cited in the main text.

²Findings as described in the paper.

³Of the two reported cases, one involved only mild liver damage, limiting assessment of causality.

⁴Elevated IgM and IgG levels were observed, with no significant change in titers after 10 days.

ANA: Anti-nuclear antibody; CD: Cluster of differentiation; Chol: Cholestatic injury; CLL: Chronic lymphocytic leukemia: DM: Diabetes mellitus; EBV: Epstein-Barr virus; FL: Fatty liver; GB: Gallbladder; γ-GTP: γ-glutamyl transpeptidase; HBsAg: Hepatitis B surface antigen: Hep: Hepatocellular injury; HC: Hypercholesterolemia; HL: Hyperlipidemia; HLH: Hemophagocytic lymphohistiocytosis; IgG4-RD: IgG4-related disease; IgG-HBcAb: Immunoglobulin G type hepatitis B core antibody; IVIG: Intravenous immunoglobulins; Mixed: Mixed injury; NA: Not available or not applicable; RA: Rheumatoid arthritis; RF: Rheumatoid factor; VA-ECMO: Venoarterial extracorporeal membrane oxygenation.