COVID-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms

Abstract

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is spreading globally and poses a huge threat to human health. Besides common respiratory symptoms, some patients with COVID-19 experience gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and loss of appetite. SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2 (ACE2) and there is increasing evidence of a possible fecal-oral transmission route. In addition, there exist multiple abnormalities in liver enzymes. COVID-19-related liver injury may be due to drug-induced liver injury, systemic inflammatory reaction, and hypoxia-ischemia reperfusion injury. The direct toxic attack of SARS-CoV-2 on the liver is still questionable. This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.

Fig. 1

Proposed model of SARS-CoV-2 structure and the life cycle of SARS-CoV-2 in host cells. a The structure of SARS-CoV-2. b The entry of SARS-CoV-2 into host cells. Transmembrane spike (S) glycoprotein forms homotrimers protruded from the surface of SARS-CoV-2 to recognize human host ACE2 protein. Receptor-binding domain (RBD) is directly involved in the recognition process. c TMPRSS2 and TMPRSS4, two mucose-specific serine proteases, can promote the infection of SARS-CoV-2 on ACE2⁺ intestinal epithelial cells. TMPRSS4 is higher expressed than TMPRSS2 in mature enterocytes, while TMPRSS2 is higher expressed than TMPRSS4 in goblet, endocrine cells. d Life cycle of SARS-CoV-2 in host cells. First, S protein of SARS-CoV-2 is combined with ACE2 to form ACE2–virus complex. SARS-CoV-2 is transported to host cells with the assistance of TMPRSS2 and TMPRSS4. Second, SARS-CoV-2 RNA is released into host cytoplasm. SARS-CoV-2 RNA conducts translation of viral polymerase proteins via host ribosome. Third, the negative (−)-sense genomic RNA is synthesized and guide synthesis of subgenomic or genomic positive (+)-sense RNA. Nucleocapsids of SARS-CoV-2 are assembled from genomic RNA and N proteins. Other structures of SARS-CoV-2 such as spike (S) protein, envelope (E) protein and membrane (M) protein are translated in the host endoplasmic reticulum (ER). Finally, the viral RNA-N complex and S, M, and E proteins enter ERGIC (endoplasmic reticulum (ER)–Golgi intermediate compartment) and produce a completely new SARS-CoV-2. The new produced SARS-CoV-2 is released from the host cell through exocytosis

Fig. 2

Patients with severe COVID-19 develop facial blackness and dull skin after recovery. Liver injury during COVID-19 is mainly responsible for these special manifestations. Three possible mechanisms are presented: (1) iron in the damaged liver drains into blood vessels. The blood with high iron level can lead to a blackening of the face once it supplies to the facial skin; (2) estrogen cannot be metabolized in the damaged liver. An increase in estrogen in the blood eventually causes an increase in conversion of tyrosine to melanin; (3) when liver function is impaired, adrenocortical function is hypoactive and melanocyte-stimulating hormone increases

Fig. 3

Mechanisms of COVID-19-associated liver injury: (1) drug-induced liver injury; (2) systemic inflammatory response (inflammatory cytokine storm); (3) hypoxic ischemia–reperfusion injury; (4) direct toxic effect of SARS-CoV-2 on the liver