Liver pathology in COVID-19 related death and leading role of autopsy in the pandemic

Table 1 Literature review results

Ref.	Country	Cases (n)	Age (mean, range)	Sex	Type of autopsy	Pre-existing liver disease or other diseases	Laboratory findings	Macroscopic results	Microscopic results	Additional stainings	Cause of death	Medications	Hospitalization	Virus identification in liver
Aguiar et al[13], 2020	Switzerland	1	31	F	Complete	Obesity	NR	Nutmeg appearance	Microabscesses	None	Respiratory failure in COVID-19	None	Home death	No search
Arslan et al[14], 2021	Turkey	7	56, 43-68	M 6, F 1	Partial	3 obesity, 2 hypertension, 1 in hemodialysis	NR	NR	4 mild steatosis, 1 biliary microhamartoma	None	Respiratory failure in COVID-19	NR	5 hospitalized, 2 NR	No search
Barton et al[15], 2020	United States	2	59, 42-77	M 2	Complete	2 obesity, 1 hypertension and 1 myotonic muscular dystrophy	NR	Case 1: weight: 2232 g, steatosis. Case 2: weight: 1683 g, cirrhosis	Nr	None	1 respiratory failure in COVID-19, 1 complications of hepatic cirrhosis	NR	1 hospitalized and 1 home death	No search
Beigmohammadi et al[16], 2021	Iran	7	68, 46-84	M 5, F 2	Core-biopsy	4 hypertension, 1 immunocompromised and 1 valvular hearth disease	NR	NR	7 congestion, 7 steatosis, 7 portal inflammation, 7 hepatitis, 4 ballooning degeneration of hepatocytes, 2 bile plugs, 7 focal confluent necrosis, 4 focal hepatocyte drop out	Masson’s trichrome: 1 case of mild fibrosis	NR	7 were treated with hydroxycholorquine and 6 with antivirals	All hospitalized	No search
Bradley et al[17], 2020	United States	14	74, 42-84	M 6, F 8	7 partial and 7 complete	5 obesity, 8 hypertension, 4 heart failure, 8 CKD	NR	Congestion	10 congestion, 9 steatosis, 1 toxic or metabolic disease, 4 centrilobular necrosis, 3 periportal inflammation	None	12 respiratory failure in COVID-19, 2 cardiovascular failure	NR	All hospitalized	2 positive and 1 negative PCR-test, 11 not tested. 14 negative IHC and TEM
Bryce et al[18], 2020	United States	92	NR	NR	Complete	28 fatty liver disease	NR	NR	8 cirrhosis, 57 early organizing thrombi in portal venules and terminal hepatic venules, 41 congestion with some cases showing hemophagocytosis	None	NR	NR	NR	No search
Bösmüller et al[19], 2020	Germany	4	72, 59-79	M 3, F 1	Complete-no brain	2 HIV, 2 hypertension	3 NR 1 with normal values	1 hepatosplenomegaly and 1 yellowish surface	Case 1: congestion and activation of Kupffer cells. Case 2: macrophages activation with signs hemophagocytosis	None	1 respiratory failure in COVID-19, 3 MOF	1 had a MOF and was intubated, 1 was treated with meropenem, 1 was treated with ECMO	3 hospitalized and 1 home death	Negative PCR-test
Bugra et al[20], 2021	Turkey	100	55, 7-98	M 80, F 20	Partial	NR	NR	NR	84 inflammation, 54 steatosis, 19 glycogenisation, 9 centilobulary necrosis, 18 autolysis, 45 congestion, 7 endotheliitis, 1 cirrhosis, 2 fibrin thrombosis, 2 bridging necrosis, 1 granulomatous inflammation, 23 cholestasis	CD3+ in portal space	74 respiratory failure in COVID-19 and 26 NR	NR	25 hospitalized, 55 home dead, 6 falling from height, 5 car accidents and 9 NR	No search
Chornenkyy et al[21], 2021	United States	8	58, 18-81	M 3, F 5	Complete	2 chronic liver disease (1 HCV and 1 autoimmune hepatitis), 6 obesity, 4 hypertension	Peak AST: 146 (20-1470) and ALT: 214 (10-9961)	Yellowish surface and congestion	3 periportal fibrosis, 2 necrosis, 5 inflammation, 7 portal inflammation, 6 congestion, 4 steatosis, 6 acute hepatitis	NR	NR	NR	All hospitalized	4 positive and 4 negative PCR-test
Danics et al[22], 2021	Hungary	100	75, 40-102	M 50, F 50	Complete	36 obesity, 6 liver diseases, 85 hypertension	41 elevated AST values and 27 elevated ALT values	Average weight 1544 g (range 520-3046 g)	63 steatosis, 43 portal fibrosis, 4 cirrhosis, 11 centrolobular necrosis, 87 congestion, 52 hepatocellular cholestasis	None	NR	NR	All hospitalized	No search
Del Nonno et al[23], 2021	Italy	3	69, 63-76	M 2, F 1	Complete	NR	Admission AST: 63 (31-128) and ALT: 41 (19-84)	NR	All cases showed steatosis, portal inflammation, portal fibrosis, focal lobular inflammation, zonal necrosis and congestion	IHC: CD8+ in portal inflammation, CD34 positive staining in the portal tract vasculature and sinusoids, Perl's staining for iron demonstrated iron deposits into hepatocytes	All respiratory failure in COVID-19	1 NR, one with immunosuppressor (tocilizumab) and one with antibiotics + morphine. All had O2 therapy (1 CPAP and 2 venturi mask)	All hospitalized	Negative PCR-test and IHC detection (nucleocapsid and nucleoprotein)
Edler et al[24], 2020	Germany	80	79, 52-96	M 46, F 34	Complete	6 obesity, 4 cirrhosis	NR	NR	Congestion	None	76 respiratory failure in COVID-19, 1 pericardial tamponade, 1 sepsis and 2 cardiovascular failure	17 with NIV	51 hospitalized, 13 in nursing care homes, 12 home deaths, 1 in a hotel and 3 NR	No search
Elsoukkary et al[25], 2020	United States	32	68, 30-100	M 22, F 10	Partial	17 hypertension, 12 obesity	AST: 567 (18-6000) and ALT: 387 (12-4885)	NR	9 steatosis, 6 portal inflammation, 3 bridging fibrosis and/or cirrhosis	None	NR	19 hydroxychloroquine and antibiotics, 9 only antibiotics	All hospitalized	No search
Evert et al[26], 2021	Germany	8	62, 44-73	M 4, F 4	Complete	7 obesity, 1 liver cirrhosis, 5 hypertension	NR	NR	7 cholestasis, 7 single-cell necrosis, 5 fatty degeneration with 2 showing marked steatosis, 2 mild fibrosis, 1 cirrhosis	None	8 MOF	All did NIV, dialysis and antibiotics. 5 had ECMO	All hospitalized	3 positive PCR-test
Falasca et al[27], 2020	Italy	22	68, 27-92	M 15, F 7	Complete	1 obesity	NR	Congestion	11 inflammation, 10 congestion, 12 steatosis	None	All respiratory failure in COVID-19	NR	All hospitalized	No search
Fassan et al[28], 2020	Italy	26	82, 61-97	M 14, F 11	Complete	5 obesity, 1 HCV-related cirrhosis	NR	NR	1 cirrhosis, 22 congestion, 5 centrilobular parenchymal atrophy, 2 fibrosis, 5 sinusoidal diffuse microthrombi, 3 portal vein thrombosis, 2 centroacinar necrosis, 26 activation of Kupffer cells, 1 portal inflammation, 9 steatosis	None	NR	NR	NR	Negative ISH
Greuel et al[29], 2021	Germany	6	35, 26-46	M 3 F 3	Complete	1 obesity, 2 right cardiac insufficiency, 1 Ewing sarcoma	4 elevated AST and ALT values	NR	1 severe cholestasis, 1 focal ischemic damage 2 steatosis	None	3 MOF, 1 acute mesenteric ischemia, 1 cardiovascular failure, 1 hemorrhagic shock	5 had ECMO and NIV	All hospitalized	Negative PCR-test
Grosse et al[30], 2020	Austria	14	82, 55-94	M 9, F 5	Complete	1 liver cirrhosis, 8 hypertension	Admission AST: 49 (12-98) and ALT: 25 (7-87)	NR	13 steatosis, 14 congestion, 12 portal lymphoid infiltration, 4 portal fibrosis	None	2 bronchopneumonia, 12 NR	12 had antibiotics	All hospitalized	No search
Hanley et al[31], 2020	United Kingdom	10	73, 52-79	M 7, F 3	Complete	5 obesity, 4 hypertension	NR	Average weight 1432 g (range 1012-2466) and 3 hepatomegaly	7 steatosis, 3 cirrhosis or bridging fibrosis	None	NR	4 NIV	All hospitalized	3 positive PCR-test (e gene)
Hirayama et al[32], 2021	United Kingdom	19	71, 42-94	M 11, F 8	Complete	5 obesity, 8 hypertension	NR	NR	12 steatosis, 5 congestion, 4 cirrhosis, 3 portal inflammation	None	NR	NR	All hospitalized	No search
Hooper et al[33], 2021	United States-Brazil	135	61	M 80, F 55	36 core-biopsy and 99 partial	34 obesity, 5 liver disease, 86 hypertension	NR	NR	41 necrosis, 37 steatosis, 19 inflammation, 7 fibrosis, 6 congestion, 5 cirrhosis, 3 cholestasis	None	101 respiratory failure in COVID-19, 6 cardiovascular failure, 28 NR	NR	All hospitalized	No search
Ihlow et al[34], 2021	Germany	1	88	F	Complete	None	Peak AST: 1690 and ALT: 1632	Subtotal liver dystrophy	Necrosis, cirrhosis, portal inflammation	IHC for ACE2, TMPESS2 and cathepsin L: strong membranous signals in intrahepatic bile duct epithelium	Acute liver failure	Antibiotics	Hospitalized	ISH positive in the bile duct epithelium and positive PCR-test
Lacy et al[35], 2020	United States	1	58	F	Complete	Obesity	NR	Weight 1990 g	Steatosis and congestion	None	Respiratory failure in COVID-19	NR	Home death	No search
Lagana et al[36], 2020	United States	40	70, 66-80	M 28, F 12	NR	2 chronic liver disease, 1 alcohol-related cirrhosis, 1 liver transplant with acute rejection and 1 with anti-HBV core antibody positivity	n = 33 Admission AST: 63 (43-92) and ALT: 32 (19 - 55). Peak AST: 102 (54-294) and ALT: 68 (32-258)	2 fibrosis and 1 had abscesses, 37 with steatosis and congestion	20 lobular necroinflammation, 20 portal inflammation, 10 lobular apoptosis, 30 steatosis, 32 congestion, 16 centrilobular necrosis, 15 cholestasis	None	NR	22 steroids, 19 hydroxychloroquine, and 6 received tocilizumab	All hospitalized	11 positive and 9 negative PCR-test
Lax et al[37], 2020	Austria	11	82, 75-91	M 8, F 3	Partial	2 obesity, 9 hypertension, 1 Hodgkin lymphoma and 1 bladder carcinoma	AST: 66 (17-189) and ALT: 41 (19-98)	NR	11 steatosis, 8 congestion, 7 necrosis, 10 Kupffer cell proliferation, 6 portal fibrosis, 8 inflammation, 8 ductular proliferation	None	Pulmonary arterial thrombosis	2 NIV, 9 AIRVO and 9 had antibiotics	All hospitalized	No search
Malik et al[38], 2021	India	1	31	F	Complete	None	NR	Congestion	Congestion, mild chronic inflammatory infiltrate in some portal tract, and occasional lymphocytic aggregate adjacent to central vein	None	Respiratory failure in COVID-19	None	Hospitalized	Positive PCR-test
Menter et al[39], 2020	Switzerland	21	76, 53-96	M 17, F 4	17 complete and 4 partial	2 chronic liver disease, 21 hypertension, 6 obesity	n = 10 AST: 67.2 (22-214)	NR	7 steatosis, 5 necrosis, 3 ASH/NASH	None	Respiratory failure in COVID-19	NR	All hospitalized	No search
Nunes et al[40], 2021	South Africa	75	60, 49-68	M 29, F 46	Core- biopsy	41 hypertension, 20 HIV	NR	NR	33 portal inflammation, 24 steatosis, 40 sinusoidal inflammation, 10 lobular hepatitis, 9 Kupffer cell activation, 11 spotty necrosis, 4 confluent necrosis, 6 fibrosis, 26 congestion, 7 fibrin-platelet thrombi	None	NR	NR	All hospitalized	No search
Oprinca[41], 2020	Romania	3	59, 27-79	M 3	1 complete and 2 partial	1 choledochal preampular intraluminal obstruction	NR	Case 1: choledochal preampullary intraluminal obstruction, case 2: normal, case 3: hepatomegaly and cirrhosis	Case 1: congestion, steatosis, periportal fibrosis and portal inflammation, case 2: nothing, case 3: bridging fibrosis and portal inflammation	None	2 respiratory failure in COVID-19, 1 shock hemorrhagic	Case 1: antibiotics, corticosteroids and assisted oxygenation. Case 2: none (home death). Case 3: none	2 hospitalized, 1 NR	No search
Rapkiewicz et al[42], 2020	United States	7	NR, 44-65	M 3, F 4	Complete	5 obesity and 7 hypertension	NR	NR	6 steatosis, 1 cirrhosis, 6 platelet-fibrin microthrombi in sinusoids, 2 necrosis	None	Cardiovascular failure	5 azithromycina and hydroxychloroquine and O2 NIV	5 hospitalized, 2 home deaths	No search
Remmelink et al[43], 2020	Belgium	17	72, 62-77	M 12, F 5	Complete	2 cirrhosis, 1 liver transplant, 10 hypertension	NR	5 hepatomegaly	7 congestion, 1 steato-necrosis, 10 steatosis, 1 cholestasis, 3 chronic hepatitis, 2 cirrhosis, 1 centro-obular necrosis	None	9 respiratory failure in COVID-19, 7 MOF and 1 NR	11 had mechanical ventilation	All hospitalized	14 positive and 3 negative PCR-test
Ren et al[44], 2021	China	1	53	F	Complete	None	Admission AST: 27 and ALT: 24. Peak AST: 83 and ALT: 93	Normal	Nothing remarkable	None	Respiratory failure with bacterial infection	She treated herself at home with Chinese herb medicine. In hospital intensive oxygen and supportive measurements, extensive antibiotics and antiviral	Hospitalized	Positive PCR-test
Schmit et al[45], 2020	Belgium	14	63, 50-83	M 10, F 4	Complete	1 HIV, 1 non-alcoholic steatohepatitis, 1 HCV-hepatitis, 6 obesity	Admission AST: 54 (15-188) and ALT: 30 (7-62). Peak AST: 2610 (15-24176) and ALT: 854 (10-7245)	Average weight 1988 g (range 1280-3220 g). 8 cases yellowish appearance 6 nutmeg appearance, 2 indurated consistency, 1 hepatocellular carcinoma, 1 normal	11 centrilobular necrosis, 9 steatosis, 8 lobular inflammation, 12 portal inflammation, 4 fibrosis, 5 bile duct proliferation, 5 cholestasis, 5 iron overload	None	13 NR and 1 acute mesenteric ischemia	8 hydroxychloroquine and antibiotics, 4 with antibiotics, 2 with hydroxychloroquine	All hospitalized	No search
Schweitzer et al[46], 2020	Switzerland	1	50	M	Complete	HIV	NR	Reduced consistency	Steatosis and liver dystrophy	None	Respiratory failure in COVID-19	None	Home death	No search
Shishido-Hara et al[47], 2021	Japan	1	75	M	Complete	None	NR	Normal	Portal inflammation	None	Severe hemorrhage	Anti-viral therapy, antibiotics, O2 therapy	Hospitalized	No search
Sonzogni et al[48], 2020	Italy	48	71, 32-86	M 22, F 8	30 partial and 18 complete - no brain	7 obesity	47 elevated values	NR	24 lobular inflammation, 32 portal inflammation, 18 confluent necrosis 18, 26 steatosis, 48 vascular thrombosis (35 portal, 13 sinusoidal), 37 fibrosis	None	NR	NR	All hospitalized	No search
Suess et al[49], 2020	Switzerland	1	59	M	Complete	None	NR	NR	Steatosis and some single necrotic hepatocytes	None	Respiratory failure in COVID-19	NR	Home death	No search
Tehrani et al[50], 2022	Iran	5	71, 55-85	M 3, F 2	Partial	None	AST: 275 (106-528) and ALT: 392 (168-978)	NR	Congestion, hepatocytes mildly expanding and bile plugs	None	4 respiratory failure in COVID-19 and 1 cardiovascular failure	1 hydroxychloroquine and antibiotics, 2 with hydroxychloroquine and anti-viral therapy, 1 only anti-viral therapy, 1 anti-viral therapy + antibiotics	All hospitalized	No search
Tian et al[51], 2020	China	4	73, 59-81	M 3, F 1	Core-biopsy	1 cirrhosis and 1 hypertension	AST: 36,4 (30-48.8) and ALT: 16 (11-25.5)	NR	Case 1: congestion, glycogen accumulation and focal steatosis, case 2: regenerative nodules and fibrous bands, lobular inflammation and Kupffer cell activation, cases 3: Kupffer cell activation, case 4: periportal and centrilobular necrosis	None	Respiratory failure in COVID-19	Antibiotics, antiviral therapy assisted oxygenation	All hospitalized	1 positive and 2 negative PCR-test, 1 was not tested
Varga et al[52], 2020	Switzerland	1	58	F	NR	Obesity and hypertension	NR	NR	Endotheliitis and necrosis	None	MOF	Dialysis	Hospitalized	No search
Wang et al[53], 2020	China	2	50 and 79	M 1, F 1	Core-biopsy	NR	Case 1 peak ALT and AST of 70 U/L and 111 U/L, respectively. Case 2 peak ALT and AST of 76 and 236 U/L	NR	Case 1: apoptotic hepatocytes, steatosis, lobular inflammation, portal inflammation, case 2: apoptotic bodies, steatosis, portal inflammation	IHC: case 1 increased CD68 + cells in hepatic sinusoids and infrequent CD4+. Case 2: many CD68+ cells in sinusoids	1 respiratory failure in COVID-19 and 1 septic shock	Both had antiviral therapy and antibiotics	All hospitalized	2 positive TEM (viral particles exist without membrane-bound vesicles)
Wang et al[54], 2020	China	1	75	F	Core-biopsy	Chronic cardiac insufficiency, hypertension	Elevated AST and ALT values	NR	Necrosis, activated histiocytes, occasional apoptotic hepatocytes, steatosis and cholestasis	None	MOF	NR	Hospitalized	Negative ISH
Xu et al[55], 2020	China	1	50	M	Core-biopsy	NR	NR	NR	Steatosis	None	Respiratory failure in COVID-19	Antibiotics, antiviral therapy and oxygenation	Hospitalized	No search
Yadav et al[56], 2022	India	21	61, 25-84	M 15, F 6	Complete	6 obesity, 1 hepatitis B, 1 multiple myeloma	Admission AST: 95.4 (18.9-760.4) and ALT: 52,1 (13,2-229,2). Peak AST: 162,6 (19,8-760,4) and ALT: 75 (21.8-229.2)	NR	20 portal inflammation, 17 steatosis, 9 lobular inflammation, 1 fibrosis, 1 vascular thrombosis, 1 necrosis	None	10 MOF, 1 multiple injuries, 6 septic shock, 3 cardiovascular failure, 1 respiratory failure in COVID-19	11 treated with antibiotics, 7 antibiotics and antiviral therapy	All hospitalized	11 positive, 9 negative PCR-test, 1 not tested
Youd et al[57], 2020	United Kingdom	9	72, 33-88	M 4, F 5	Complete	3 obesity	NR	4 congestion, 1 steatosis and 4 normal	NR	None	Respiratory failure in COVID-19	NR	9 deaths in community settings	No search
Zhao et al[58], 2020	United States	17	65, 44-85	M 10, F 7	Complete	5 hyperlipidemia, 1 cirrhosis	12 elevated AST and ALT values. Peak AST: 1903 (24-13592) and ALT 1059 (13-6136)	Weight 17694 g (1000-2600 g)	12 platelet-fibrin microthrombi, 5 histiocyte activation, 12 steatosis, 5 lobular inflammation, 8 portal inflammation, 10 necrosis	CD68 stain confirmed histiocytic hyperplasia	NR	NR	All hospitalized	5 positive IHC (spike protein) in the histiocytes in the portal tracts. Negative IHC in endothelial cells and hepatocytes

F: Female; Male: M; HCV: Hepatitis C virus; NIV: Non-invasive ventilation; ECMO: Extracorporeal membrane oxygenation; COVID-19: Coronavirus disease 2019; AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; ISH: In situ hybridization; MOF: Multi-organ failure; PCR: Polymerase chain reaction; TEM: Transmission electron microscopy; NR: Not reported; IHC: Immunohistochemistry.

Table 2 Laboratory findings

Laboratory findings	Mean (UI/L)	Range (UI/L)
Admission values (n = 53)
AST	58	12-760
ALT	34	7-229
Peak values (n = 64)
AST	868	15-24176
ALT	509	10-9961
Non specified
AST (n = 61)	202	17-6000
ALT (n = 51)	209	11-4885

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

Table 3 Microscopic findings

Microscopic findings	n (%)
Hepatic necrosis	190 (19)
Hepatic inflammation	190 (19)
Portal inflammation	178 (18)
Fibrosis	149 (15)
Microthrombi	121 (12)
Cholestasis	114 (11)
Hemophagocytosis	51 (5)
Bile plugs	2 (0.2)
Endotheliitis	7 (0.7)
Autolysis	20 (2)
Iron overload	5 (0.5)
Other (abscess, ductal proliferation and granulomatosis)	15 (1.5)