COVID-19 vaccination and liver disease

Table 1 Summary of coronavirus disease 2019 vaccines

Corporation	Vaccine	Mechanism	Vaccination Group: Number of cases/number of vaccinations (%)	Invaccination Group: Number of cases/number of vaccinations (%)	Efficacy % (95%CI)
Pfizer-BioNTech[18]	BNT162b2	mRNA	8/21720 (0.037)	162/21728 (0.746)	95.0 (90.3-97.6)
Moderna[20]	mRNA-1273	mRNA	11/15210 (0.072)	185/15210 (1.216)	94.1 (89.3-96.8)
Oxford-AstraZeneca[25]	ChAdOx1 nCoV-19 (AZD122)	Vector	27/4440 (0.608)	71/4455 (1.594)	62.1 (41.0-75.7)
Johnson & Johnson[26]	Ad26.COV2.S	Vector	433/19113 (2.265)	883/18924 (4.666)	52.9 (47.1-58.1)
Sinovac Life Science[29]	Corona Vac	Inacctivated	9/6559 (0.137)	32/3470 (0.922)	83.5 (65.4–92.1)

Table 2 Literature review of the efficacy and safety of coronavirus disease 2019 vaccines in patients with liver disease

Ref.	Design	Vaccine	Country/region	Number of participants	Value	Major findings (efficacy)	Major findings (safety)
Cirrhosis
John et al[45], 2021	Multicentre retrospective cohort study	BNT162b2 and mRNA-1273	United States	Cirrhosis group (n = 20037); Control (n = 20037)	Efficacy	64.8% decrease in the development of COVID-19 infection after the first dose and a 78.6% decrease after the second dose	NA
Thuluvath et al[46], 2021	Prospective cohort study	BNT162b2, mRNA-1273, and AZD1222	United States	LT (n = 62); Cirrhosis (n = 79); CLD (n = 92)	Immunogenicity	Antibody was detectable in 82.2% of LT recipients, 96.2% of cirrhosis and 95.7% of CLD without cirrhosis. 61.3% of LT recipients and 24% CLD with/without cirrhosis had poor antibody responses	No patient had any serious AEs
Ruether et al[47], 2022	Prospective cohort study	BNT162b2, mRNA-1273, and AZD1222	Germany	LT (n = 138); Cirrhosis (n = 48); Control (n = 52)	Immunogenicity	Immunological response rates were 36.6%, 65.4%, and 100% in LT, cirrhosis, and controls, respectively	NA
Willuweit et al[48], 2022	Prospective cohort study	BNT162b2	Germany	Cirrhosis (n = 166); Control (n = 79)	Immunogenicity	Antibody was detectable in 96% of cirrhosis and 99% of controls. The median SARS-CoV-2 IgG titer was significantly lower in cirrhosis compared to the controls (939 vs 1905 BAU/mL, P = 0.0001)	NA
Wang et al[49], 2022	Multicentre retrospective cohort study	Inactivated vaccine	China	Compensated-cirrhosis (n = 388); Decompensated cirrhosis (n = 165)	Immunogenicity	Antibodies were detectable in 71.6% and 66.1% in compensated-cirrhosis and decompensated-cirrhosis	The vaccines were well tolerated, most AEs were mild and transient
Ai et al[50], 2022	Multicentre prospective cohort study	Inactivated vaccine	China	CLD (n = 284); Compensated cirrhosis (n = 123); Decompensated cirrhosis (n = 30)	Immunogenicity	Antibody detection rates were 76.8% in noncirrhotic CLD group, 78.9% in compensated cirrhotic group, 76.7% in decompensated cirrhotic group, and 90.3% in controls (P = 0.008 vs CLD)	There was no significant difference in AE among subgroups
Liver transplant recipients
Rabinowich et al[51], 2021	Multicentre retrospective cohort study	BNT162b2 mRNA vaccine	Israel	LT patients (n = 80); Control (n = 25)	Immunogenicity	Immunogenicity among LT recipients was significantly lower [47.5% (LT) vs 100% (control), P < 0.001]	No patient had any serious AEs
Herrera et al[52], 2021	Multicentre prospective cohort study	mRNA-1273	Spain	LT recipients (n = 58)	Immunogenicity	93% of patients developed immunologic responses to mRNA-1273 vaccine	No serious AEs were reported in LT recipients
Strauss et al[53], 2021	Multicentre retrospective cohort study	BNT162b2 and mRNA-1273	United States	LT recipients (n = 161)	Immunogenicity	Antibody was detectable in 34% (95%CI: 27%-42%) of participants after first dose, and in 81% (95%CI: 74%-87%) after second dose	NA
Nazaruk et al[54], 2021	Retrospective cohort study	BNT162b2 mRNA vaccine	Poland	LT recipients (n = 65)	Immunogenicity	Antibody detection rate was 88.9% in LT recipients after the second dose	NA
Timmermann et al[55], 2021	Retrospective cohort study	mRNA vaccines	Germany	LT recipients (n = 118)	Immunogenicity	The seroconversion rate was 78.0% in LT recipients. MMF for immunosuppression was risk factors for seronegativity	NA
D'Offizi et al[56], 2022	Retrospective cohort study	BNT162b2 and mRNA-1273	Italy	LT patients (n = 61); Control (n = 51)	Immunogenicity	Immunological response rates 2 wk after 2nd dose were 47.5% (LT) and 100% (control) (P < 0.001)	NA
John et al[57], 2022	Multicentre retrospective cohort study	BNT162b2 and mRNA-1273	United States	LT patients (n = 1133); Control (n = 791)	Efficacy	Vaccination with 2 doses of an mRNA vaccine was associated with a 64% decrease in COVID-19 infection and 87% decrease in COVID-19–related death in LT recipients	NA
Davidov et al[58], 2022	Retrospective cohort study	BNT162b2 mRNA vaccine	Israel	LT patients (n = 76); Control (n = 174)	Immunogenicity	Immunological response rates 2 wk after 2nd dose were 72.0% (LT) and 94.2% (control) (P < 0.001)	AEs were reported by 51% LT recipients. No serious events were reported
Sakai et al[59], 2022	Retrospective cohort study	BNT162b2	Japan	LT patients (n = 56); Control (n = 42)	Immunogenicity	LT recipients showed a lower seroconversion rate (44/56; 78.6%) than healthy controls (41/42; 97.6%)	NA
Calleri et al[60], 2022	Retrospective cohort study	BNT162b2 and mRNA-1273	Italy	Pre-LT patients (n = 89)	Immunogenicity	In the 89 pre-LT patients, seroconversion rate was 94.4% (23 d after vaccination), and 92.0% (68 d after vaccination)	No serious AEs were reported in participants
Viral hepatitis and NAFLD
Xiang et al[61], 2021	Retrospective cohort study	Inactivated vaccine	China	CHB patients (n = 149)	Immunogenicity	The seroconversion rate was 87.2% in CHB	No serious AEs were reported in participants
He et al[62], 2022	Cross-sectional observational study	Inactivated vaccine	China	CHB patients (n = 362); Control (n = 87)	Immunogenicity	The seroconversion rates of SARS-CoV-2 antibodies were similar between CHB patients and healthy controls	The incidence was similar between CHB patients and controls. No serious AE
Wang et al[63], 2021	Multicentre retrospective cohort study	Inactivated vaccine	China	NAFLD patients (n = 381)	Immunogenicity	The inactivated COVID-19 vaccine was good immunogenicity (95.5%) in patients with NAFLD	AEs within 7 d and within 28 d totaled 95 (24.9%) and 112 (29.4%), respectively. No serious AEs were recorded
Autoimmune liver disease
Duengelhoef et al[64], 2022	Prospective cohort study	BNT162b2, mRNA-1273, and AZD1222	Germany	AIH (n = 103); PSC (n = 64); PBC (n = 61); Control (n = 95)	Immunogenicity	Seroconversion was measurable in 97% of AIH and 99% of PBC/PSC patients, respectively. In 14% of AIH patients antibody levels were lower compared to PBC/PSC or controls	NA
Schneider et al[65], 2022	Prospective cohort study	BNT162b2 mRNA vaccine	Austria	AIH (n = 12); Control (n = 24)	Immunogenicity	Patients of AIH and healty controls acquired sufficient antibodies after third vaccination	NA

AE: Adverse event; AIH: Autoimmune hepatitis; CHB: Chronic hepatitis B; CLD: Chronic liver disease; LT: Liver transplant; MMF: Mycophenolate mofetil; NA: Not available; NAFLD: Non-alcoholic fatty liver disease; PBC: Primary biliary cholangitis; PSC: Primary sclerosing cholangitis; CI: Confidence interval.

Table 3 Reported cases of liver injury following coronavirus disease 2019 vaccination

Ref.	Age/sex	Past history	Vaccine	Onset	AST/ALT (U/ L)	Total bilirubin (mg/ dL)	IgG	Antibody	Biopsy	Diagnose	Treatment	Outcome
Bril et al[87]	35/F	Third month postpartum	BNT162b2	7 d after the1st dose	754/2001	4.8	Normal	ANA: 1:1280	Interface hepatitis, rosette formation, eosinophil infiltration	Typical for AIH	Prednisone (20 mg/d)	Improved
Lodato et al[88]	43/F	Dyslipidemia	BNT162b2	15 d after the 1st dose	52/51	17.54	Normal	ANA: negative	Moderate portal inflammatory infiltrate with interface hepatitis, biliary injury	Compatible with AIH	Methyl-prednisolone (1 mg/kg/d)	Improved
Vuille-Lessard et al[89]	76/F	Hashimoto's disease, urothelial carcinoma	mRNA-1273	3 d after the 1st dose	811/579	3.8	Increased	ANA: 1:1280, AMA: 1:1280	Interface hepatitis, plasma cells infiltration, pseudorosettes	Compatible with AIH	Prednisolone (40 mg/d) + azathioprine	Improved
Londoño et al[90]	41/F	Premature ovarian failure	mRNA-1273	7 d after the 2nd dose	993/1312	2.3	Increased	ANA: 1:80	Interface hepatitis with a lymphoplasmacytic infiltrate	Typical for AIH	Prednisone (1 mg/kg)	Improved
Rocco et al[91]	80/F	Hashimoto's disease	BNT162b2	7 d after the 3rd dose	1401/1186	10.5	Increased	ANA: 1:160	Interface hepatitis with a lymphoplasmacytic infiltrate	Typical for AIH	Prednisone	Improved
McShane et al[92]	71/F	Osteoarthritis	mRNA-1273	4 d after the 1st dose	-/1067	15.7	Increased	ASMA: 1:2560	Interface hepatitis, eosinophil infiltration	Compatible with AIH	Prednisolone (40 mg/d)	Improved
Clayton-Chubb et al[93]	36/M	Hypertension	AZD1222	26 d after the 1st dose	633/1774	9.9	Normal	ANA: 1:160	Interface hepatitis	Compatible with AIH	Prednisolone (60 mg/d)	Improved
Tan et al[94]	56/F	None	mRNA-1273	35 d after the 1st dose	1124/1701	5.9	Increased	ANA: positive, ASMA: Positive	Interface hepatitis, rosette formation, eosinophil infiltration	Compatible with AIH	Budesonide	Improved
Ghielmetti et al[95]	63/M	Type 2 diabetes, ischemic heart disease	mRNA-1273	7 d after the 1st dose	1127/1038	11.9	Increased	ANA: 1:640	Inflammatory portal infiltrate with interface hepatitis	Typical for AIH	Prednisone (40 mg/d)	Improved
Zhou et al[96]	36/F	Ulcerative colitis, primary sclerosing cholangitis	mRNA-1273	11 d after the 1st dose	581/588	1.4	Increased	ANA: 1:2560	Interface hepatitis with a lymphoplasmacytic infiltrate, rosette, eosinophil	Compatible with AIH	Prednisone (50 mg/d)	Improved
Garrido et al[97]	65/F	JAK2 V617F-positive polycythemia	mRNA-1273	14 d after the 1st dose	1056/1092	1.1	Increased	ANA: 1:100	Interface hepatitis	Compatible with AIH	Prednisolone (60 mg/d)	Improved
Goulas et al[98]	52/F	None	mRNA-1273	14 d after the 1st dose	350/936	9.06	Increased	ANA: 1:320, ASMA: positive	Portal, periportal inflammation, rosette formation	Typical for AIH	Prednisolone (50 mg/d) + azathioprine	Improved
Rela et al[99]	38/F	Hypothyroidism	AZD1222	20 d after the 1st dose	1101/1025	14.9	Increased	ANA: positive	Multiacnar hepatic necrosis and periportal neocholangiolar proliferation	Compatible with AIH	Prednisolone (30 mg/d)	Improved
Rela et al[99]	62/M	None	AZD1222	13 d after the 2nd dose	1361/1094	19.2	NA	ANA: negative	Portal neocholangiolar proliferation and mild to moderate inflammation	Compatible with AIH	Prednisolone (30 mg/d) + plasma exchange	Death
Palla et al[100]	40/F	Sarcoidosis	BNT162b2	28 d after the 2nd dose	4 times upper limit of normal	NA	Increased	ANA: 1:640	Interface hepatitis with plasma cells infiltration	Compatible with AIH	Prednisolone (40 mg/d)	Improved
Mann et al[101]	61/F	Irritable bowel disease, cholecystectomy	BNT162b2	9 d after the 2nd dose	37/37	6.2	NA	ANA: negative	Scattered inflammatory cells consisting of lymphocyte and few eosinophils	Drug induced liver injury	Conservative treatment	Improved
Avci et al[102]	61/F	Hashimoto's disease, hypertension	BNT162b2	28 d after the 1st dose	455/913	11.8	Increased	ANA: 1:100, ASMA: 1:100	Interface hepatitis	Compatible with AIH	Prednisolone (40 mg/d) + azathioprine	Improved
Torrente et al[103]	46/F	Hypothyroidism, anemia	AZD1222	21 d after the 1st dose	241/353	Normal	Increased	ANA: 1:160	Lymphoplasmacytic portal infiltrate	Compatible with AIH	Prednisone (30 mg/d) + azathioprine	Improved
Ghorbani et al[104]	62/M	None	Corona Vac	3 d after the 2nd dose	722/435	8	NA	ANA: negative, ASMA: negative	Interface hepatitis, infiltration of lymphocytes and eosinophils in portal tract	Compatible with AIH	Ursodeoxycholic acid	Improved
Kang et al[105]	27/F	None	BNT162b2	7 d after the 2nd dose	1004/1478	8.6	Increased	ANA: 1:80	Interface hepatitis with a lymphoplasmacytic infiltrate, rosette, eosinophil	Typical for AIH	Prednisolone (40 mg/d)	Improved
Camacho-Domínguez et al[106]	79/M	None	AZD1222	15 d after the 1st dose	2003/1994	11.9	Increased	ANA: 1:80	Interface hepatitis with a lymphocytic infiltrate, eosinophil	Compatible with AIH	Prednisone (30 mg/d) + azathioprine	Improved
Shahrani et al[107]	59/F	Dyslipidemia	AZD1222	12 d after the 2nd dose	962/1178	7.5	Increased	NA	Lympho-plasmacellular portal infiltrate	Compatible with AIH	Prednisolone (40 mg/d)	Improved
Shahrani et al[107]	63/F	Ulcerative colitis, primary sclerosing cholangitis	AZD1222	14 d after the 1st dose	505/354	18.6	Increased	ANA: positive	Interface hepatitis	Compatible with AIH	Prednisolone (40 mg/d)	Improved
Shahrani et al[107]	72/F	None	BNT162b2	10 d after boostershot	1452/2280	1.7	Increased	ANA: negative, AMA: positive	Infiltration of lymphocytes and plasma cells in portal tract	Compatible with AIH	Prednisolone (40 mg/d)	Improved
Zin Tun et al[108]	47/M	None	mRNA-1273	3 d after the 1st dose; A few days after the 2nd dose	NA/1048	11.3	Increased	ANA: positive	Interface hepatitis with a lymphoplasmatic infiltrate, rosette, emperipolesis	Typical for AIH	Prednisolone (40 mg/d)	Improved
Suzuki et al[109]	80/F	Gastroesophageal reflux esophagitis	BNT162b2	10 d after the 2nd dose	995/974	3.5	Increased	ANA: 1:40	Lymphoplasmacytic infiltration in the portal area, interface hepatitis	Compatible with AIH	Prednisone (0.8 mg/kg/d)	Improved
Suzuki et al[109]	75/F	Dyslipidemia	BNT162b2	4 d after the 2nd dose	1085/820	17.7	Increased	ANA: 1:80	Lymphoplasmacytic infiltration in the portal area, interface hepatitis	Compatible with AIH	Prednisone (1.0 mg/kg/d)	Improved
Suzuki et al[109]	78/F	Primary biliary cholangitis	BNT162b2	7 d after the 1st dose	401/542	1.3	Increased	ANA: 1:80	Lymphoplasmacytic infiltration in the portal area, interface hepatitis	Compatible with AIH	Prednisone (0.6 mg/kg/d)	Improved

AIH: Autoimmune hepatitis; AMA: Anti-mitochondrial antibodies; ANA: Anti-nuclear antibodies; ASMA: Anti-smooth muscle antibodies; JAK: Janus kinase; NA: Not available; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; IgG: Immunoglobulin G.