Research progress on COVID-19 combined with digestive system diseases

Shan-Shan Liu, Li-Ting Zheng, Yin-Nan Kang, You-Cheng Xie, Gang-Gang Jia,Jiu-Cong Zhang, Xiao-Hui Yu

1. The First Clinical Medical School, Gansu University of Chinese Medicine, Lanzhou 730000,China

2. Department of Gastroenterology, The 940 Hospital of Joint Service Support Forces of the Chinese People's Liberation Army, Lanzhou 730050, China

3. Lanzhou University, Lanzhou 730000, China

Keywords:COVID-19 SARS-CoV-2 ACE2 receptor Digestive system

ABSTRACT The corona virus disease 2019 (COVID-19) is an acute respiratory infection caused by the binding of SEVERE acute respiratory syndrome coronavirus 2 (SARS-COV-2) and the angiotensin-converting enzyme 2 (ACE2) receptor to the host target organ. New research suggests that COVID-19 may be a systemic infectious disease and a systemic inflammatory disease.Symptoms and signs of the digestive system are often found in patients with coVID-19 following acute infection.At present, despite the existence of some coronavirus-related digestive diseases (such as gastrointestinal diseases, liver injury, pancreatic injury, etc.), the pathogenesis of COVID-19 with digestive symptoms in existing studies is still unclear, and relevant guidelines and expert consensus are not enough for clinical diagnosis and treatment.Therefore, it is extremely important to understand the clinical manifestations, pathogenesis and prognosis of coVID-19 patients with digestive system.✉Corresponding author: YU Xiao-hui, Professor, Chief Physician, M.D.. Doctoral Supervisor.

The novel coronavirus pneumonia (COVID-19) is a Type B infectious disease with widespread prevalence, severe symptoms and poor prognosis. In addition to lung injury, it also causes damage to the functions of multiple organs such as the liver, spleen, brain,kidney and gastrointestinal tract. It brings certain difficulties to clinical treatment and management and is a key problem for aggravation of the disease and poor prognosis of patients.And there are literature reports[1]Compared with patients without gastrointestinal symptoms, patients with gastrointestinal symptoms had longer hospital stays and poorer prognosis.Although a variety of potentially effective antiviral drugs, vaccines, cell therapies,traditional Chinese medicines and other methods are in clinical trials, there is still no specific drug for COVID-19.Therefore, it is of great importance to understand the injury of the digestive system associated with COVID-19 and its possible mechanism. Relevant literature is summarized to improve our understanding of the injury of the digestive system associated with COVID-19, so as to improve the level of clinical diagnosis and treatment and reduce the fatality rate of patients.

1. Overview of SARS-COV-2

Sars-cov-2 belongs to the coronavirus family and is a singlestranded RNA virus. Sars-cov-2 virus is composed of four major structural proteins: spike protein (S), membrane protein (M),nucleocapsid protein (N) and envelope protein (E).[2-3], where S protein is a key component in mediating the entry of virus into host cells[4]It's not.Sars-cov-2 entry into cells depends on S protein binding to specific cell receptors and host cell protease initiation of S protein.During cell infection, most coronavirus S proteins are cut into S1 receptor-binding subunits and S2 fusion subunits by host cell Flynn (Furin-like) proteases[5]It's not.S1 contains a receptor binding domain (RBD), which plays an important role in the recognition and binding of ACE2.The S2 subunit is associated with the fusion of virus and host cell membranes.After the receptor binding domain in the S1 domain binds to the cell receptor ACE2, transmembrane serine protease type 2 (TMPRSS2) is triggered to cut protein S at sites S1 and S2, resulting in membrane fusion so that the virus can enter the cell and replicate in the cell.Since cell surface receptors and mediators are important in determining the host and invading organ of the virus, the route of SARS-COV-2 infection and the organ infected may depend on the expression and distribution of ACE2 and TMPRSS2[6]It's not.Hoffmannetal etal[4]It was confirmed that the entry of SARS-COV-2 into host cells is dependent on THE SARSCOV receptor ACE2 and this entry can be blocked by clinically proven inhibitors of TMPRSS2.

Sars-cov-2 activates the host's innate and adaptive immune responses and causes acute inflammatory responses, which may lead to local and systemic tissue damage.In fact, symptoms associated with SARS-COV-2 infection occur not only in the respiratory system, but also in the digestive system.Digestive system involvement is defined as having at least one of the following symptoms[7], including loss of appetite, nausea, vomiting, diarrhoea (loose stools ≥3 times per day),abdominal pain, abdominal distension or gastrointestinal bleeding(vomiting blood, black stools), etc.Although the gastrointestinal,liver, and pancreas of some COVID-19 patients are less severe, sarSCOV-2 virus RNA can be detected in the stool of patients, indicating the presence of the virus in the gastrointestinal tract infection,replication, and detachment from the gastrointestinal tract, which has important implications for disease management, transmission, and infection control.In addition, sarS-COV-2 induced liver injury, acute decompensation, acute or chronic liver failure, and pancreatic injury may alter the outcome of the disease.

2. CoVID-19 with gastrointestinal symptoms

2.1 Epidemiology of COVID-19 with gastrointestinal symptoms

There are regional differences in the frequency of symptoms of the digestive system in coVID-19 patients[8]North America was higher,followed by Europe and Asia.Compared to Chinese patients[9], non-Chinese patients are more likely to experience diarrhea, nausea/vomiting, and abdominal pain, and cultural differences, dietary habits, innate immunity, and various other factors may influence clinical presentation.Pan[1]Et al. found that the incidence of anorexia,diarrhea, vomiting, and abdominal pain in severe COVID-19 patients was 100%, 21.4%, 7.14%, and 0%, respectively, while the incidence of abdominal pain was higher in critically ill patients (8.70%).This suggests that patients with severe and critical COVID-19 are more likely to have symptoms of the digestive system.But there is no evidence that symptoms of the digestive system indicate further progress.

2.2 The mechanism of gastrointestinal symptoms after SARSCOV-2 infection

(1)Direct damage to cells in the gastrointestinal tract The entry of SARS-COV-2 virus into host cells is the main link of cross-species transmission.All coronaviruses bind to receptors and mediate their entry through glycoproteins and spike proteins[10]It's not. A number of studies have shown that[6], S protein of SARSCOV-2 has high affinity for ACE2 receptor on host cell membrane and enters host cells through ACE2 receptor.TMPRSS2 can cut the S protein of SARS-COV-2, so as to promote the fusion of SARSCoV-2 and cell membrane.ACE2 and TMPRSS2 are reported to be co-expressed in the gastrointestinal tract, including esophageal and glandular cells and absorbable intestinal epithelial cells from the ileum and colon[11], which provides the fundamental conditions for SARS-COV-2 virus to enter cells.When the virus enters the cell,the RNA is translated, and the viral proteins are synthesized into new virions that are released in the gastrointestinal tract[12], leading to direct rupture of intestinal cells, further changing intestinal permeability, resulting in malabsorption and intestinal secretion imbalance, and thus leading to diarrhea[13]It's not.Other studies have shown that[14], SARS-COV-2 infection also destroys the tight junctions and adhesion between endothelial cells and intestinal epithelial cells, which may lead to bowel leakage syndrome, local and systemic invasion of normal microbiota members, and immune activation.

CD147, also known as Basigin (encoded by BSG and a transmembrane receptor), is another susceptibility factor that may play a role in SARS-COV-2 infection and is expressed in tissues such as the lung and intestine.CD147 may be involved in GASTROINTESTINAL SARS-COV-2 infection and may play a role in the presence of low ACE2 expression.Daria Bortolotti et al[15]A SARS-COV-2SP binding site co-localized with CD147 expression was found in intestinal tissue, supporting its role as a susceptibility factor for SARS-COV-2 infection in the intestinal tract.

(2) Cytokine storm

"Cytokine storm" is an abnormal, dynamic inflammatory response to external stimuli and is thought to be an important mechanism for multiple organ dysfunction in COVID-19 patients.High levels of pro-inflammatory cytokines, including interferon - (IFN-), interferon- (IFN-), and interleukin-5 (IL-5), are detected in the serum of most coVID-19 patients[16]It's not.The primary cause of cytokine storm after COVID-19 infection is the induction of various proinflammatory signals by antigen-presenting cells and virus-infected T cells, as well as the activation of macrophages and dendritic cells.He et al.[17]PIC of pro-inflammatory cytokines such as tumor growth factor -1, monocyte chemokine -1 (McP-1), tumor necrosis factor- (TNF-), IL-1, and IL-6 were found to be highly expressed in cells expressing ACE2, but not PIC in cells not expressing ACE2.Another study shows that[18]In comparison with patients with mild and moderate clinical symptoms, levels of cytokines and chemical attractants (IL-5, IL-6, IL-7, IL-13, IL-15, IL-18, TNF-) were significantly higher in severe patients.Further analysis of ICU and non-ICU patient findings[16], plasma LEVELS of IL-2, IL-7, IL-10,G-CSF, IP10, MCP1, MIP1A, and TNF were higher in ICU patients than in non-ICU patients.These studies suggest that cytokine levels may be highly correlated with the severity of multisystem disease in coVID-19 patients.

In the intestinal tract where ACE2 is highly expressed, ACE2 ACTS as a regulator of dietary amino acid homeostasis, particularly tryptophan (Trp).Trp catabolism through the canine urine (Kyn)pathway plays an important role in regulating the balance between effectors and immune responses.The Kyn pathway provides the raw material for the synthesis of nicotinamide adenine dinucleotide(NAD), which is important for regulating oxidative stress and DNA damage repair.Qin et al.[19]Results showed that changes in the Kyn pathway impaired the immune system's negative self-regulation,thereby promoting excessive inflammation and cytokine storm syndrome, which made COVID-19 more lethal, and they found that serum Trp and Kyn levels were significantly lower in COVID-19 patients than in healthy and non-COVID-19 patients.However,more evidence is needed to unify the definition of cytokine storm in COVID-19, as there is much debate as to whether COVID-19 should be included in the cytokine storm spectrum.

(3) Intestinal microecological disorder

The human gastrointestinal microbiota consists of more than 1014A microbe composed primarily of bacteria but also containing populations of archaea, fungi, protozoans, and viruses[20]It's not.Intestinal microecology is closely related to multisystem diseases including the digestive system.Studies have found that[21]In the gastrointestinal tract, ACE2 plays its role not through the reninangiotensin-aldosterone system (RAAS) but by regulating the intake of intestinal amino acids, the production of antimicrobial peptides,and the composition of gastrointestinal microflora.ACE2 protein expression was down-regulated after SARS-COV-2 virus infection.The deficiency of ACE2 is due to the binding of the spike S protein of SARS-CoV-2 to the extracellular domain of ACE2, which can lead to the internalization of ACE2/BOAT1 (a neutral amino acid transporter), which limits the role of ACE2 as carboxylpeptidase of peptide hormones such as angiotensin II (AngII) and deargininebradykinin[22]It's not.ACE2 controls the expression of B0AT1,a major apical membrane transporter in the intestinal tract,allowing Na+The conjugate ingested neutral amino acids, such as tryptophan[23]It's not.B0AT1 substrates, such as tryptophan and glutamine, maintain the integrity of tight intestinal junctions,activate the release of antimicrobial peptides, and regulate mucosal autophagy[24]It's not.ACE2 down-regulation can reduce intestinal absorption of tryptophan and secretion of antimicrobial peptides,thereby promoting pathogen survival and intestinal flora imbalance.Yeoh et al. found that[25]The composition of the intestinal microflora of coVID-19 patients during hospitalization is associated with plasma concentrations of several cytokines, chemokines, and inflammatory markers, suggesting that the intestinal microflora may play a role in regulating host immune responses and may influence disease severity and outcomes.Another study shows that[26], the diversity of the intestinal DNA virus group of COVID-19 patients was significantly reduced, which also reflects the intestinal microbiota disorder of COVID-19 patients.The influence of intestinal flora on mucosal immunity is not limited to the gastrointestinal tract.In fact, they can also affect the immune response of the far mucous membranes outside the intestine, including the lungs, thus exacerbating the symptoms of the disease.The above evidence supports the hypothesis that SARS-COV-2 infection affects host microbial composition and immunity.

(4) Side effects of drugs

Antibiotics are often used in the initial treatment of SARS-COV-2 infection, which may cause intestinal flora imbalance in patients.Lu et al. 's research suggests that[27], antibiotics had a significant effect on the human enterovirus group.Diarrhoea caused by antibiotics(including cephalosporins, macrolides and -lactams) is the most common adverse side effect of antimicrobial agents.Other antiviral drugs that may cause diarrhea during the treatment of COVID-19[28], including lopinavir, chloroquine phosphate, Redesivir and proprietary Chinese medicines (such as Lianhua Qingwen Capsule).Ramachandran et al[29]Patients exposed to PROTON pump inhibitors(PPI) were found to have poorer clinical outcomes regardless of cardiovascular disease prior to admission.This may be because stomach acid inactivates most virus particles.If a person USES PPI for a long period of time to suppress gastric acid production, the pH in the stomach will be reduced and SARS-COV-2 may also enter the gut faster, leading to a viral infection.

3. CoVID-19 with liver injury

3.1 Epidemiology of COVID-19 associated with liver injury

Covid-19-related liver injury is defined as liver injury occurring in coVID-19 patients, regardless of pre-existing liver disease[30]It's not.Recent studies have shown that[16], the incidence of liver injury in COVID-19 patients ranged from 14.8% to 53%, mainly manifested as abnormal ALT/AST levels accompanied by slightly elevated bilirubin levels, and about 26.3～30.9g/L of albumin in severe patients.A multicenter study involving 1,099 patients and 552 hospitals found that[31], liver injury is more common in severe patients than in patients with mild COVID-19.Another case study involving 1100 patients with COVID-19 infection also found[32]Elevated AST and ALT levels are higher in severe cases than in mild to moderate cases, especially elevated AST, which reflects not only liver damage but also multiple organ damage and is closely associated with the risk of death from COVID-19.Together, these data suggest that an increase in the severity of COVID-19 infection exacerbates liver damage and is associated with the prognosis of major adverse clinical outcomes.Therefore, the degree of liver injury can be used as an indicator to predict the progression of COVID-19.However, the etiology of COVID-19 combined with liver injury is multifactorial, and the specific causes are not yet clear.

3.2 The mechanism of COVID-19 combined with liver injury

(1) Direct cytotoxic effect It has been determined that SARS-COV-2 enters host cells through S protein binding to ACE2 receptors on the host cell surface[33]It's not.Sars-cov-2 can lead to viral cytopathic effects through direct immune damage to hepatocytes, accompanied by microvesicular steatosis and hepatic lobule or portal vein invasion[34]It's not.Ultrastructural changes in hepatocytes infected with SARS-COV-2 included endoplasmic reticulum expansion, mitochondrial swelling and glycogen granule reduction.In addition, extensive hepatocyte apoptosis and abnormal binuclear cells can also be observed in the liver tissues of infected patients, and CD4 in the liver tissues of patients infected with SARS-COV-2 can be identified by immunohistochemistry+And CD8+Lymphocytic deficiency[35]It's not.

However, it is based on single-cell sequencing and animal model analysis[36], ACE2 expression level in liver tissues is about 0.31%,while its expression level in bile duct cells is 20 times that in liver cells.This suggests that sarS-COV-2 target cells may be bile duct cells rather than hepatocytes.But the study found that[37]In the transition from mild to severe liver injury, the increase in ALP (a measure of bile duct injury) is not as severe as the increase in AST and ALT.Therefore, we cannot conclude that COVID-19 liver injury is driven by the direct tropism of bile duct cells.

(2) Inflammatory response syndrome and cytokine storm

Sars-cov-2 infection causes immune cells such as macrophages,neutrophils, and lymphocytes to overproduce a range of cytokines(such as TNF-, IL-6, IL-8, etc.), leading to systemic inflammatory response syndrome and acute respiratory distress syndrome, leading to ischemia and hypoxia, and ultimately cell destruction and necrosis, a process known as cytokine storm[38]It's not.Cytokine storm is one of the main characteristics of coVID-19 patients and may be a risk factor for disease severity and death.Proinflammatory agents in patients with COVID-19[39]Levels of il-1, IL-7, IL-8,IL-9, IL-10, TNF- and other inflammatory factors were significantly higher than in healthy adults.In addition, serum inflammatory cytokines levels were found to be positively correlated with liver dysfunction, suggesting a potential mechanism between liver injury and inflammatory response[40]It's not.As one study found[41],compared with patients without severe COVID-19, patients with severe COVID-19 had an increased IL-6 value, and the increase was more obvious in patients with COVID-19 combined with abnormal liver function.And before reaching the threshold of severe liver injury, although both procalcitonin and ferritin are elevated,we know that procalcitonin, ferritin and lactate dehydrogenase(LDH) are associated not only with systemic inflammation, but also with bacterial infection. Therefore, the observed increase of these indicators may be the result of coVID-19 combined with bacterial infection or secondary systemic inflammatory response syndrome[42]It's not.

(3) Endothelial cell injury

Covid-19 is considered an inflammatory thrombotic disease that affects not only the lungs but also the endothelial cells.Endothelial cells are one of the most abundant cells in the human body. Vascular endothelium is essential to regulate vascular tension and maintain vascular homeostasis. Intact endothelial cells can provide effective anticoagulant properties.When vascular endothelial cells are infected by viruses or destroyed directly by immune-mediated inflammation,vasoconstriction and procoagulant behavior occur rapidly, potentially leading to microthrombi.The production of microthrombus may affect the liver blood flow and induce liver dysfunction[43]It's not.And in critically ill coVID-19 patients[44], liver dysfunction may also occur due to hemodynamic changes due to heart failure/mechanical ventilation, leading to vascular lesions, enddermatitis,and clotting disease.In addition, SARS-COV-2 infection may induce acute lung injury or acute respiratory distress syndrome, leading to the production of hypoxemia and hyperfibrinogenemia, leading to endothelial dysfunction[45]And induce liver damage.Spiezia et al[46]It was found that plasma fibrinogen and D-dimer levels were significantly higher in severe COVID-19 patients than in healthy controls, which also indicated that the balance between coagulation and anticoagulation was disturbed in patients with COVID-19 complicated with liver injury.

(4) Previous liver disease worsened Obesity and chronic diseases, including liver disease, are associated with induction of pro-inflammatory states and impaired immune response disorders, which may increase susceptibility to SARSCOV-2 infection and the risk of serious complications.Previous liver diseases of major concern in COVID-19 include chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), autoimmune hepatitis, and compensatory and decompensated cirrhosis.Pre-existing chronic liver disease appears to be an independent risk factor for poor prognosis for COVID-19[47], studies have shown[48]Subjects with prior chronic liver disease (for example, non-alcoholic fatty liver disease with fibrosis or cirrhosis) are at a high risk of developing severe COVID-19 because their ACE2 expression levels are elevated, leading to a greater likelihood of SARS-COV-2 virus passing through liver cells.Alqahtani et al[49]A meta-analysis conducted showed that patients with a history of liver disease had a 57.33% chance of being cured of COVID-19 infection, but patients with a history of liver disease associated with COVID-19 infection had a 17.65% higher mortality rate than patients with coVID-19 infection alone.A multicenter study of 867 patients with chronic liver disease and coVID-19[50], 14.0%died, 60.4% were hospitalized, 23% were admitted to intensive care units, and 7.7% developed liver decompensation.In another study,1,099 patients with COVID-19 were enrolled[31], 23 (2.1%) patients developed hepatitis B (HBV) infection, while COVID-19 patients with HBV were more likely to progress, and COVID-19 patients with HBV or hepatitis C virus (HCV) infection were found to be more likely to develop severe hepatitis, possibly due to increased viral replication during SARS-COV-2 infection.These data indicate that the incidence of acute decompensation and acute/chronic liver failure after sarS-COV-2 infection in patients with pre-existing chronic liver disease is higher than that of patients with normal COVID-19.Cirrhosis in patients with SARS-COV-2 infection was described as a predictor of mortality[51]It's not.A study shows that[51],the mortality rate was 32% in patients with a history of cirrhosis and 8% in patients without a history of cirrhosis (P<0.001).Patients with cirrhosis complicated by SARS-COV-2 infection appear to be a particularly lethal combination.Because cirrhosis may impair the liver's homeostasis role in the systemic immune response, it may affect the elimination of SARS-COV-2, leading to a diminished therapeutic effect of COVID-19.(5) Drug-induced liver injury Drug-induced liver injury during treatment (DILI)[52]It is defined as liver damage caused by the drug and/or its metabolites, or hypersensitivity or reduced tolerance to the drug due to special constitution during the administration of the drug. Patients with metabolic syndrome and liver steatosis infected with coronavirus are more likely to develop drug-induced liver injury[53]It's not.Certain COVID-19 therapies may also be hepatotoxic, including antivirals,antibiotics, steroids, anticoagulants, and immunomodulatory drugs.Montastruc et al[54]Compared with other drugs, Reddisivir increased the risk of liver damage.In another retrospective study[55], lopinavir/ritonavir had a seven-fold higher risk of liver injury than patients who did not take the drug.Other studies have reported that targeted drugs such as ACE inhibitors and angiotensin II receptor blockers can lead to elevated liver enzyme levels in coVID-19 patients, which also indicates that liver damage has occurred during the use of these drugs[56]It's not.Research findings[57]Azithromycin and tozumab (an IL-6 inhibitor) also induce liver damage, and liver damage induced by these two drugs can heal on its own.All of these drugs can cause liver damage during the treatment of COVID-19. Although there is no strong evidence that liver damage in these patients is caused solely by drugs, the value of optimizing drug use in managing COVID-19 cannot be ignored.

4. Covid-19 with pancreatic injury

4.1 Epidemiology of COVID-19 combined with pancreatic injury

A recent study reports[58]About 17% of patients with COVID-19 pneumonia experience pancreatic injury defined by amylase or lipase abnormalities.Of the 52 hospitalized patients with COVID-19 pneumonia, 17% had biochemical evidence of pancreatic injury(increased amylase and lipase)[58], but no structural damage to the pancreas, such as edema, necrosis of the pancreas, peripancreatic fat retention or effusion, was determined, as no imaging studies were performed in this observational study. Therefore, it is speculated that pancreatic injury in patients with COVID-19 pneumonia may be due to direct viral involvement of the pancreas or secondary enzyme abnormalities resulting from severe systemic disease.

4.2 The mechanism of COVID-19 combined with pancreatic injury

(1) Direct cell damage Liu et al.[59]The pancreas was found to be a potential target organ for COVID-19 infection.Since the co-expression of ACE2 and TMPRSS2 is crucial for the successful infection of SARS-COV-2,and the content of ACE2 and TMPRSS2 is relatively high in exocrine pancreatic duct cells, the infection of these cells may be one of the reasons for the coVID-19 complicated pancreatic injury[60]It's not.However, itis still not clear whether SARS-COV-2 infection causes Acute Pancreatitis (AP), or aggravates the inflammatory response, leading to increased risk of organ failure and pancreatic complications, leading to increased morbidity and mortality in patients.Pancreas cells do not co-express ACE2 and TMPRSS2, so it is not clear whether SARS-COV-2 directly/indirectly affects cell function.However, changes in glucose metabolism and diabetes associated with COVID-19 appear to be multifactorial and may be caused by systemic inflammation and metabolic changes in other organs, including liver, muscle and adipose tissue, rather than simply the result of pancreatic injury.Studies have shown that[61-62]Sarscov-2 infection increases the risk of idiopathic acute pancreatitis but does not increase the risk of long-term diabetes.

(2)Systemic inflammatory response syndrome

Studies have shown that SARS-COV-2 rapidly activates T cells and induces the release of a variety of inflammatory cytokines, such as granulocyte-macrophage colony stimulating factor (GM-CSF),IL-1, IL-6, monocyte chemoattractant protein-1, and IFN-.And GMCSF can activate CD14+Cell, CD16+Cells and monocytes, thereby increasing levels of inflammatory cytokines and accelerating the inflammatory cascade. This strong immune response can lead to tissue damage[63]It's not. Meanwhile, high IL-6 levels are associated with an increased risk of severe pancreatitis[64]It's not.In addition,cytokine storms that occur after SARS-COV-2 infection can cause chronic persistent stimulation of target organs, which is thought to lead to ferritin elevation and many damaging remodeling changes,such as chronic fibrosis that may affect islet and cell function.

(3) Ischemic pancreatic injury

After the cytokine storm associated with severe COVID-19 cases, inflammatory cells migrate to inflammation/infection sites,promoting a pro-inflammatory feedback loop.Tissue factors on platelets, white blood cells, and endothelial cells are up-regulated,external and internal clotting pathways are activated, and thrombin production and microthrombus formation are promoted, leading to hypoperfusion and ischemia.But in order to protect blood flow to vital organs such as the brain and heart, the body reduces blood flow to the abdominal cavity, the superior mesenteric artery and the inferior artery, followed by the renal and iliac arteries.This is the neurohormonal mechanism that protects vital organs. The pancreas is supplied by the pancreatic arteries from the spleen,gastroduodenum, and superior mesenteric arteries.Amylase, lipase,aspartic acid aminotransferase (AST), and lactate dehydrogenase(LDH) are released into the blood when reduced blood flow to the pancreas leads to ischemic damage to the pancreas, resulting in elevated levels of these enzymes in the blood[65], followed by an inflammatory response and acute pancreatitis[66]It's not.The damage was caused primarily by hemodynamic deterioration, rather than by the virus itself. It has been reported that pancreatic ischemia may be the cause of different degrees of acute pancreatitis. Local coagulation may lead to mild AP. In more severe AP cases, the imbalance between coagulation and anticoagulation may lead to disseminated intravascular coagulation (DIC).[67]It's not.(4) Increased trypsin caused by renal failure

Glomerular filtration is responsible for the removal of serum amylase and lipase, and since the kidney plays a vital role in the removal of amylase and lipase from the circulatory system, renal dysfunction, even temporarily, can lead to transient increases in trypsin.Chen et al.[68]The incidence of amylase and lipase elevations above the normal upper limit in CHRONIC renal failure was found to be 35.7% and 26.2%, respectively, which confirms the previous hypothesis, but more evidence is needed to verify the role of renal dysfunction in pancreatic injury.

(5)Hyperlipidemia

Studies have reported that[69], the incidence of hyperlipidemia in COVID-19 patients ranged from 0.30% to 81.82%.Moreover,hyperlipidemia is common in patients with severe COVID-19, and its underlying causes may be as follows: hemophagocytosis, drug therapy, and acute liver injury.Previous studies have shown that[70],the potential mechanism of hypertriglyceridemia in the deterioration of AP may be the accumulation of free fatty acids, thereby activating the inflammatory response in the pancreas.It is reported that[71], free fatty acids can lead to elevated levels of inflammatory mediators such as TNF-, IL-6, IL-10, etc., which may enhance systemic inflammatory responses and local pancreatic injury.Two cases of hypertriglyceridemia due to tozumab during COVID-19 treatment have also been reported[71], and one of them developed AP in the late course.This suggests that hyperlipidemia is associated with COVID-19-induced AP.However, it remains to be investigated whether coVID-19 patients with hyperlipidemia have a higher INCIDENCE of AP than coVID-19 patients without hyperlipidemia.

(6) Previous history of pancreatic injury

Pancreatic acinus cells release a variety of cytokines, including TNF, IL-6, and IL-10, during acute pancreatitis, while T cells and macrophages are heavily involved in the inflammatory process of chronic pancreatitis.Preactivation of immune cells in the pancreatic microenvironment may increase the risk of more severe inflammatory responses during COVID-19 infection[72]It's not.A recent study showed that[73]Patients with SARS-COV-2 positive AP had significantly increased risks of moderate to severe or severe AP,local complications, acute respiratory distress syndrome, persistent sexual organ failure, prolonged ICU stay, and high 30-day mortality.It is also noteworthy that the 30-day mortality rate (14.7%) of AP patients with SARS-COV-2 infection was significantly higher than that of AP patients without SARS-COV-2 infection (2.6%).These data further suggest that in patients with a history of acute or chronic pancreatitis, SARS-COV-2 infection may exacerbate pancreatic inflammation and may contribute to disease progression.And Arcus[74]Et al reviewed a group of 127 patients with elevated lipase levels during COVID-19.The study showed that patients infected with SARS-COV-2 had a high risk of developing elevated pancreatic enzymes, especially those who already had diabetes.With the ongoing SARS-COV-2 pandemic, patients with reduced normal pancreatic function continue to have an increased risk of coVID-19 infection and require hospitalization.In particular,elevated blood sugar levels in diabetics and non-diabetics put them at high risk of death[75]It's not. Hyperglycemia impinges on immune responses (for example, by reducing the activity of macrophages and polymorphonuclear white blood cells), in addition to affecting excessive cytokine responses, and is therefore highly pro-inflammatory.Furthermore, transient cell dysfunction caused by SARS-COV-2 infection may also lead to uncontrolled hyperglycemia, especially in patients whose pancreas is already affected by diabetes.

(7) Drug-induced pancreatic injury Drug-induced pancreatitis is defined as pancreatitis that occurs after the introduction of a drug or shortly after an increased dose without the typical causes of pancreatitis, such as cholelithiasis, metabolism,and alcohol[76]It's not.Some drugs are toxic to the pancreas and can even cause drug-induced pancreatitis, such as antivirals (lopinavir and ritonavir), antipyretics, and tozumab baritinib[77]It's not.Existing therapies for coVID-19 treatment may also cause pancreatic damage,including corticosteroids, antiviral drugs (such as remivir) and antibiotics (such as linezolid)[78-79]It's not.Studies have reported that[80], tozumab (TCZ), lopinavir/ritonavir, and propofol infusion in critically ill patients can lead to hypertriglyceridemia in coVID-19 patients, which in turn may lead to pancreatitis.Another study found that[81], one of the mechanisms of AP formation in COVID-19 patients may be the administration of glucocorticoids (GCS)upon admission to the ICU with severe respiratory failure.These drugs may be responsible for the elevation of pancreatic lipase rather than the direct effect of the virus on the pancreas. Regardless of the etiology of pancreatic injury, more importantly, it remains to be determined whether elevated lipase in COVID-19 patients is associated with disease severity and can independently predict clinical outcomes.

5. Summary and Prospect

Covid-19 is a disease caused by SARS-COV-2 that threatens public health worldwide.Respiratory system is the main target of SARS-COV-2 attack.The main clinical symptoms of COVID-19 are associated with pneumonia and are characterized by severe acute respiratory distress syndrome.At the same time, the digestive system is also at high risk of being invaded by SARS-COV-2,because the ACE2 receptor mediating THE entry of SARS-COV-2 into cells is highly expressed in the gastrointestinal tract. However,high expression of ACE2 may bring benefits. For example, ACE2 in the circulation can bind to SARS-COV-2 and remove it from the circulation.In addition, the increased expression of ACE2 may promote self-dimerization on the cell membrane and reduce the affinity, internalization and reproduction of the virus.Finally,increased ACE2 levels may divert the renin-angiotensin system(RAS) to vascular protective function.Together, these findings underscore the potential of ACE2 as a target for the treatment of COVID-19 and the need for future research in this area.

The feces of some patients contained infectious SARS-COV-2,indicating that SARS-COV-2 could be transmitted through the fecal-oral route.Therefore, for some patients with first symptoms of digestive system, medical staff should not take it lightly. They should always be vigilant, so as not to miss the diagnosis and cause the rapid and widespread spread of the virus.At the same time,for patients with COVID-19 combined with digestive symptoms,clinicians should pay close attention to the changes of patients'condition, because the digestive symptoms and the prognosis of coVID-19 patients' course of disease have not been determined.At the same time, we know that sarS-COV-2's most destructive force is the production of violent cytokine storms that cause systemic inflammatory response syndrome, which may account for the poor prognosis of COVID-19 patients.Therefore, an approach against invasive cytokines may also be a viable treatment for COVID-19 with digestive diseases.

Authors’ contribution

Liu Shanshan: Writing and revising the paper;Zheng Liting and Kang Yinnan: Responsible for reviewing and revising the paper;Xie Youcheng, Jia Gang: Responsible for data sorting;Zhang Jiucong and Yu Xiaohui: Responsible for paper design and topic selection,data sorting and analysis