Efeitos histopatológicos e imunológicos potenciais do SARS-CoV-2 no fígado

Alnamshan, M. M.

M. M. Alnamshan ^**e-mail: malnamshan@iau.edu.sa

Imam Abdulrahman Bin Faisal University, College of Science, Department of Biology, Dammam, Saudi Arabia

http://orcid.org/0000-0002-9277-3996

*e-mail: malnamshan@iau.edu.sa

Figuras (4)
Tabelas (1)

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Figure 1
SARS-CoV-2 structure and life cycle adapted from Zhong et al. (2020)ZHONG, P., XU, J., YANG, D., SHEN, Y., WANG, L., FENG, Y., DU, C., SONG, Y., WU, C., HU, X. and SUN, Y., 2020. Covid-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms. Signal Transduction and Targeted Therapy, vol. 5, no. 1, p. 256. http://dx.doi.org/10.1038/s41392-020-00373-7. PMid:33139693.
http://dx.doi.org/10.1038/s41392-020-003... .

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Figure 2
Potential mechanisms of hepatic injury with SARS-CoV-2 infection adapted from Yang et al. (2020)YANG, R.X., ZHENG, R.D. and FAN, J.G., 2020. Etiology and management of liver injury in patients with covid-19. World Journal of Gastroenterology, vol. 26, no. 32, pp. 4753-4762. http://dx.doi.org/10.3748/wjg.v26.i32.4753. PMid:32921955.
http://dx.doi.org/10.3748/wjg.v26.i32.47... .

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Figure 3
Immune-mediated liver injury adapted from Spearman et al. (2021)SPEARMAN, C.W., AGHEMO, A., VALENTI, L. and SONDERUP, M.W., 2021. Covid-19 and the liver: a 2021 update. Liver International, vol. 41, no. 9, pp. 1988-1998. http://dx.doi.org/10.1111/liv.14984. PMid:34152690.
http://dx.doi.org/10.1111/liv.14984... .

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Figure 4
The major liver histological features adapted from Díaz et al. (2020)DÍAZ, L.A., IDALSOAGA, F., CANNISTRA, M., CANDIA, R., CABRERA, D., BARRERA, F., SOZA, A., GRAHAM, R., RIQUELME, A., ARRESE, M., LEISE, M.D. and ARAB, J.P., 2020. High prevalence of hepatic steatosis and vascular thrombosis in covid-19: a systematic review and meta-analysis of autopsy data. World Journal of Gastroenterology, vol. 26, no. 48, pp. 7693-7706. http://dx.doi.org/10.3748/wjg.v26.i48.7693. PMid:33505145.
http://dx.doi.org/10.3748/wjg.v26.i48.76... .

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Table 1
A list of the histological liver abnormalities found in SARS-CoV-2 patients.

Reference	Country	Sample size	Histopathological abnormalities
Wang et al. (2020e)WANG, Y., LIU, S., LIU, H., LI, W., LIN, F., JIANG, L., LI, X., XU, P., ZHANG, L., ZHAO, L., CAO, Y., KANG, J., YANG, J., LI, L., LIU, X., LI, Y., NIE, R., MU, J., LU, F., ZHAO, S., LU, J. and ZHAO, J., 2020e. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with covid-19. Journal of Hepatology, vol. 73, no. 4, pp. 807-816. http://dx.doi.org/10.1016/j.jhep.2020.05.002. PMid:32437830. http://dx.doi.org/10.1016/j.jhep.2020.05...	Beijing and Anhui province, China	156 (2 liver tissues only)	Apoptosis in the liver and some binuclear hepatocytes. Small numbers of CD4+ and CD8+ cells. S protein forms in the cytoplasm of hepatocytes with evident mitochondrial expansion, endoplasmic reticulum dilatation, and glycogen granule decrease typical of coronavirus infection. Increased CD68+ cells were primarily found in the hepatic sinusoids, indicating Kupffer cell activation.
Ji et al. (2020)JI, D., QIN, E., XU, J., ZHANG, D., CHENG, G., WANG, Y. and LAU, G., 2020. Non-alcoholic fatty liver diseases in patients with covid-19: a retrospective study. Journal of Hepatology, vol. 73, no. 2, pp. 451-453. http://dx.doi.org/10.1016/j.jhep.2020.03.044. PMid:32278005. http://dx.doi.org/10.1016/j.jhep.2020.03...	China	202	Damage to the liver was hepatocellular rather than cholestatic. Microvesicular steatosis and T cell overactivation were found in one patient.
Xu et al. (2020c)XU, Z., SHI, L., WANG, Y., ZHANG, J., HUANG, L., ZHANG, C., LIU, S., ZHAO, P., LIU, H., ZHU, L., TAI, Y., BAI, C., GAO, T., SONG, J., XIA, P., DONG, J., ZHAO, J. and WANG, F.S., 2020c. Pathological findings of covid-19 associated with acute respiratory distress syndrome. The Lancet. Respiratory Medicine, vol. 8, no. 4, pp. 420-422. http://dx.doi.org/10.1016/S2213-2600(20)30076-X. PMid:32085846. http://dx.doi.org/10.1016/S2213-2600(20)...	Beijing, China	1	Minimal lobular and portal activity, moderate microvesicular steatosis.
Lagana et al. (2020a)LAGANA, S.M., KUDOSE, S., IUGA, A.C., LEE, M.J., FAZLOLLAHI, L., REMOTTI, H.E., PORTILLO, A., MICHELE, S., GONZALEZ, A.K., SAQI, A., KHAIRALLAH, P., CHONG, A.M., PARK, H., UHLEMANN, A.C., LEFKOWITCH, J.H. and VERNA, E.C., 2020a. Hepatic pathology in patients dying of covid-19: a series of 40 cases including clinical, histologic, and virologic data. Modern Pathology, vol. 33, no. 11, pp. 2147-2155. http://dx.doi.org/10.1038/s41379-020-00649-x. PMid:32792598. http://dx.doi.org/10.1038/s41379-020-006...	Columbia	40	Varying degrees of steatosis, congestion, and ischemia, but no other significant gross pathology. Granulomatous inflammation. The portal and lobular granulomas resembled a “fibrin ring” shape.
Sonzogni et al. (2020)SONZOGNI, A., PREVITALI, G., SEGHEZZI, M., ALESSIO, M.G., GIANATTI, A., LICINI, L., MOROTTI, D., ZERBI, P., CARSANA, L., ROSSI, R., LAURI, E., PELLEGRINELLI, A. and NEBULONI, M., 2020. Liver histopathology in severe covid 19 respiratory failure is suggestive of vascular alterations. Liver International, vol. 40, no. 9, pp. 2110-2116. http://dx.doi.org/10.1111/liv.14601. PMid:32654359. http://dx.doi.org/10.1111/liv.14601...	Bergamo, Italy	48	Inflammatory infiltrates and lobular lymphocytes were dispersed throughout the portal area, with varying degrees of portal vein endotheliitis and only mild to moderate portal fibrosis; the biliary intrahepatic tree showed no major histological changes.
Tian et al. (2020)TIAN, S., XIONG, Y., LIU, H., NIU, L., GUO, J., LIAO, M. and XIAO, S.Y., 2020. Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies. Modern Pathology, vol. 33, no. 6, pp. 1007-1014. http://dx.doi.org/10.1038/s41379-020-0536-x. PMid:32291399. http://dx.doi.org/10.1038/s41379-020-053...	Wuhan, China	4	Mild lobular infiltration by small lymphocytes and centrilobular sinusoidal dilation. Patchy necrosis was also observed.
Zhang et al. (2020b)ZHANG, Y., ZHENG, L., LIU, L., ZHAO, M., XIAO, J. and ZHAO, Q., 2020b. Liver impairment in covid-19 patients: a retrospective analysis of 115 cases from a single centre in Wuhan city, China. Liver International, vol. 40, no. 9, pp. 2095-2103. http://dx.doi.org/10.1111/liv.14455. PMid:32239796. http://dx.doi.org/10.1111/liv.14455...	Wuhan, China	115	Mild sinusoidal dilatation and minor lymphocytic infiltration were observed in the liver tissue.
Duarte-Neto et al. (2020)DUARTE-NETO, A.N., MONTEIRO, R.A.A., SILVA, L.F.F., MALHEIROS, D.M.A.C., OLIVEIRA, E.P., THEODORO-FILHO, J., PINHO, J.R.R., GOMES-GOUVÊA, M.S., SALLES, A.P.M., OLIVEIRA, I.R.S., MAUAD, T., SALDIVA, P.H.N. and DOLHNIKOFF, M., 2020. Pulmonary and systemic involvement in covid-19 patients assessed with ultrasound-guided minimally invasive autopsy. Histopathology, vol. 77, no. 2, pp. 186-197. http://dx.doi.org/10.1111/his.14160. PMid:32443177. http://dx.doi.org/10.1111/his.14160...	Sao Paulo, Brazil	first 10 fatal cases	Liver macrovesicular steatosis, central coagulative necrosis, and sinusoidal congestion with fibrin thrombi.
Elsoukkary et al. (2021)ELSOUKKARY, S.S., MOSTYKA, M., DILLARD, A., BERMAN, D.R., MA, L.X., CHADBURN, A., YANTISS, R.K., JESSURUN, J., SESHAN, S.V., BORCZUK, A.C. and SALVATORE, S.P., 2021. Autopsy findings in 32 patients with covid-19: a single-institution experience. Pathobiology: Journal of Immunopathology, Molecular and Cellular Biology, vol. 88, no. 1, pp. 56-68. http://dx.doi.org/10.1159/000511325. PMid:32942274. http://dx.doi.org/10.1159/000511325...	New York, NY, USA	32	Steatosis was the most common finding, explained by the presence of obesity, diabetes, or hyperlipidemia. Nonspecific portal-based moderate lymphocytic inflammation was detected. Signs of chronic liver disease, including bridging fibrosis and cirrhosis with an unknown cause.
Falasca et al. (2020)FALASCA, L., NARDACCI, R., COLOMBO, D., LALLE, E., CARO, A., NICASTRI, E., ANTINORI, A., PETROSILLO, N., MARCHIONI, L., BIAVA, G., D’OFFIZI, G., PALMIERI, F., GOLETTI, D., ZUMLA, A., IPPOLITO, G., PIACENTINI, M. and NONNO, F., 2020. Postmortem findings in Italian patients with covid-19: a descriptive full autopsy study of cases with and without comorbidities. The Journal of Infectious Diseases, vol. 222, no. 11, pp. 1807-1815. http://dx.doi.org/10.1093/infdis/jiaa578. PMid:32914853. http://dx.doi.org/10.1093/infdis/jiaa578...	Rome, Italy	22	Sinusoidal congestion and red blood cell extravasation into the Disse space, small vein congestion, and hepatocyte death with inflammatory cell infiltration. Macrovacuolar and microvacuolar steatosis.
Fassan et al. (2021)FASSAN, M., MESCOLI, C., SBARAGLIA, M., GUZZARDO, V., RUSSO, F.P., FABRIS, R., TREVENZOLI, M., PELIZZARO, F., CATTELAN, A.M., BASSO, C., NAVALESI, P., FARINATI, F., VETTOR, R. and TOS, A.P.D., 2021. Liver histopathology in covid-19 patients: a mono-institutional series of liver biopsies and autopsy specimens. Pathology, Research and Practice, vol. 221, p. 153451. http://dx.doi.org/10.1016/j.prp.2021.153451. PMid:33932720. http://dx.doi.org/10.1016/j.prp.2021.153...	Padua, Italy	3	Except for one cirrhotic sample, all showed well-preserved lobular architecture. A zone 3 sinusoidal ectasia with significant red cell congestion and parenchymal degeneration in the centrilobular. Pericellular and sinusoidal fibrosis are two types of fibrosis. It was found that there were sinusoidal diffuse platelet-fibrin microthrombi and portal vein thrombosis. Ischemic liver necrosis of the centroacinar type. Kupffer cells were activated.
McConnell et al. (2021)MCCONNELL, M.J., KAWAGUCHI, N., KONDO, R., SONZOGNI, A., LICINI, L., VALLE, C., BONAFFINI, P.A., SIRONI, S., ALESSIO, M.G., PREVITALI, G., SEGHEZZI, M., ZHANG, X., LEE, A.I., PINE, A.B., CHUN, H.J., ZHANG, X., FERNANDEZ-HERNANDO, C., QING, H., WANG, A., PRICE, C., SUN, Z., UTSUMI, T., HWA, J., STRAZZABOSCO, M. and IWAKIRI, Y., 2021. Liver injury in covid-19 and IL-6 trans-signaling-induced endotheliopathy. Journal of Hepatology, vol. 75, no. 3, pp. 647-658. http://dx.doi.org/10.1016/j.jhep.2021.04.050. PMid:33991637. http://dx.doi.org/10.1016/j.jhep.2021.04...	New Haven, CT, USA	68	Dilated sinusoids with liver congestion, neutrophil infiltration, steatosis, and sinusoidal erythrocyte aggregation in zone 2.
Schmit et al. (2021)SCHMIT, G., LELOTTE, J., VANHAEBOST, J., HORSMANS, Y., VAN BOCKSTAL, M. and BALDIN, P., 2021. The liver in covid-19-related death: protagonist or innocent bystander? Pathobiology, vol. 88, no. 1, pp. 88-94. http://dx.doi.org/10.1159/000512008. PMid:33108789. http://dx.doi.org/10.1159/000512008...	Saint-Luc, Brussels, Belgium	78	In 12 cases, lobular and portal inflammation were observed (86%). In the portal region, two patients showed a mixed infiltration with neutrophils, and one patient had a primarily eosinophilic infiltrate. Except for one patient already diagnosed with NASH, fibrosis was often nonexistent or distinct. Five cases (36%) had a distinct iron excess, and two had ceroid macrophages. Cholestasis was detected in five cases, while distinct canalicular growth was observed in another five (36%). Endotheliitis and vascular thrombi were not observed.
Li et al. (2021)LI, Q., WANG, J., ZHOU, X., LU, H., LU, M. and HUANG, L., 2021. Case report: viral pneumonia could prompt the advancement of immune-mediated liver disease. Frontiers in Medicine, vol. 8, p. 582620. http://dx.doi.org/10.3389/fmed.2021.582620. PMid:34079806. http://dx.doi.org/10.3389/fmed.2021.5826...	Zhejiang, China	3	Lymphoid follicles collected and expanded due to lymphocytic infiltration in the portal tract. Immunolabeling with CD34 and Warthin-Starry staining was used to detect cirrhosis.
Beigmohammadi et al. (2021)BEIGMOHAMMADI, M.T., JAHANBIN, B., SAFAEI, M., AMOOZADEH, L., KHOSHAVI, M., MEHRTASH, V., JAFARZADEH, B. and ABDOLLAHI, A., 2021. Pathological findings of postmortem biopsies from lung, heart, and liver of 7 deceased covid-19 patients. International Journal of Surgical Pathology, vol. 29, no. 2, pp. 135-145. http://dx.doi.org/10.1177/1066896920935195. PMid:32552178. http://dx.doi.org/10.1177/10668969209351...	Tehran, Iran	7	Mild to moderate micro- and macro-vesicular steatosis was observed. Hepatocytes in four of the patients showed mild ballooning degeneration. Two patients had both focal and distributed bile clogs. There was focal confluent necrosis and focal hepatocyte dropout. Masson’s trichrome special staining was typical. Reticulin staining showed focal regeneration sites. There was no evidence of the viral cytopathic impact in the liver tissue slices.

[1] *e-mail: malnamshan@iau.edu.sa

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Efeitos histopatológicos e imunológicos potenciais do SARS-CoV-2 no fígado

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