Review Open Access
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2021; 27(28): 4504-4535
Published online Jul 28, 2021. doi: 10.3748/wjg.v27.i28.4504
Gastrointestinal and hepatic diseases during the COVID-19 pandemic: Manifestations, mechanism and management
Dina Zakaria Mohamed, Mai El-Sayed Ghoneim, Sally El-Sayed Abu-Risha, Ramy Ahmed Abdelsalam, Mohamed Abdelhalem Farag
Dina Zakaria Mohamed, Sally El-Sayed Abu-Risha, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31511, Egypt
Mai El-Sayed Ghoneim, Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Sadat City, Menoufia 32632, Egypt
Ramy Ahmed Abdelsalam, Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura 35511, Egypt
Mohamed Abdelhalem Farag, Department of Pediatrics, Nebru General Hospital, Nebru 35511, Egypt
ORCID number: Dina Zakaria Mohamed (0000-0003-4003-2800); Mai El-Sayed Ghoneim (0000-0002-5651-5877); Sally El-Sayed Abu-Risha (0000-0001-8099-0590); Ramy Ahmed Abdelsalam (0000-0003-1289-2862); Mohamed Abdelhalem Farag (0000-0002-2533-4600).
Author contributions: All authors contributed equally to the conception and topics for this review and to revising the article critically for intellectual content; all authors approved the final version of the manuscript for submission.
Conflict-of-interest statement: The authors have no conflicts of interest to declare. The authors only are responsible for the content and writing of the article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dina Zakaria Mohamed, MSc, Assistant Lecturer, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, El-Geish Street, Tanta 31511, Egypt. m_halem1986@yahoo.com
Received: January 15, 2021
Peer-review started: January 15, 2021
First decision: January 31, 2021
Revised: February 12, 2021
Accepted: June 7, 2021
Article in press: June 7, 2021
Published online: July 28, 2021

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered the causative pathogen of coronavirus disease 2019 (COVID-19) and has become an international danger to human health. Although respiratory transmission and symptoms are still the essential manifestations of COVID-19, the digestive system could be an unconventional or supplementary route for COVID-19 to be transmitted and manifested, most likely due to the presence of angiotensin-converting enzyme 2 (ACE2) in the gastrointestinal tract. In addition, SARS-CoV-2 can trigger hepatic injury via direct binding to the ACE2 receptor in cholangiocytes, antibody-dependent enhancement of infection, systemic inflammatory response syndrome, inflammatory cytokine storms, ischemia/reperfusion injury, and adverse events of treatment drugs. Gastrointestinal symptoms, including anorexia, nausea, vomiting, and diarrhea, which are unusual in patients with COVID-19, and some digestive signs may occur without other respiratory symptoms. Furthermore, SARS-CoV-2 can be found in infected patients’ stool, demonstrating the likelihood of transmission through the fecal-oral route. In addition, liver function should be monitored during COVID-19, particularly in more severe cases. This review summarizes the evidence for extra-pulmonary manifestations, mechanisms, and management of COVID-19, particularly those related to the gastrointestinal tract and liver.

Key Words: COVID-19, Angiotensin-converting enzyme 2, Gastrointestinal, Inflammatory bowel disease, Liver, Management

Core Tip: The coronavirus disease 2019 (COVID-19) pandemic has affected millions worldwide, with high lethality. In addition to typical respiratory symptoms of COVID-19, gastrointestinal and hepatic symptoms have been frequently observed in COVID-19 patients. The main purpose of this article is to focus on the manifestations, mechanisms, and management of the gastrointestinal tract and liver that occurred during the course of COVID-19. Therefore, physicians must not undervalue the digestive symptoms during COVID-19 and rapidly adjust the treatment options for COVID-19 patients with gastrointestinal symptoms and liver enzyme abnormalities.



INTRODUCTION

Coronaviruses (CoV) is the largest group of spike-like viruses in the Nidovirales family. In the last two decades the CoVs have caused three worldwide outbreaks, with the most recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which has resulted in coronavirus disease 2019 (COVID-19). The first 21st century outbreak in Guangdong Province, China, in November 2002, caused by SARS-CoV (SARS-CoV-1), an extreme SARS, resulted in 8098 fatalities (9.6%) globally[1,2]. The second outbreak in Saudi Arabia in 2012 was caused by Middle East respiratory syndrome (MERS)-CoV, with 2521 (36%) confirmed deaths[3].

SARS-CoV-2 first originated in China in December 2019 and critically threatened worldwide health[4,5]. On February 12, 2021, 108 million cases and 2 million deaths have been recorded in over 219 countries and regions worldwide[6]. The lung is the primary organ involved in COVID-19 pneumonia, and most COVID-19 patients suffer typical respiratory symptoms (e.g., dyspnea, cough with sputum production, fatigue, and in severe cases, acute respiratory distress syndrome (ARDS), respiratory failure, and even death). On the other hand, extrapulmonary clinical manifestations of COVID-19 affect multiple other organs including cardiovascular (e.g., arrhythmias, myocarditis, pericarditis, acute coronary syndrome, and heart failure), renal (e.g., acute kidney injury and acute tubular necrosis), hepatic [e.g., elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and bilirubin], gastrointestinal (e.g., diarrhea, nausea, vomiting, and abdominal pain), ocular (e.g., epiphora, conjunctivitis, and chemosis), dermatologic (e.g., erythematous rash, urticaria, and chickenpox-like vesicles), and neurological systems (e.g., headache, neuropathy, encephalopathy, cerebrovascular disorders, and dizziness)[7] (Figure 1). Considering all the previously mentioned data, this article examines the effects of gastrointestinal (GI) and hepatic symptoms, their associated mechanisms, and management caused by SARS-CoV-2 infection and provides a guide for clinical prevention and treatment (Figure 2).

Figure 1
Figure 1 Pulmonary and extrapulmonary manifestations of coronavirus disease 2019. ARDS: Acute respiratory distress syndrome; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase. Headache and urticaria spelled wrongly.
Figure 2
Figure 2 Mechanisms and manifestations of coronavirus disease 2019 in the gut and liver. SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ACE2: Angiotensin-converting enzyme 2; GIT: gastrointestinal tract; ADE: Antibody-dependent enhancement of infection; SIRS: Systemic inflammatory response syndrome; I/R: Ischemia and hypoxia reperfusion injury.
DISEASE COURSE OF COVID-19

For SARS-CoV-2, the incubation period is an average of 4-5 d, with most patients having symptoms before 14 d, although there have been instances where the incubation period was longer[8]. The infection and hospitalization onset was documented from 9.1 to 12.5 d and emphasizes the difficulty in the early stage of the diagnosis and isolation of populations[9]. The average period for recovering patients from initial symptoms is 22 d, and for those who succumbed the time to death is approximately 18.5 d[9].

Overall, the case fatality ratio of COVID-19 is reported to be around 1-2% in patients aged 80 years, to over 15%[10]. Currently, WHO data show that most COVID-19 cases have mild to moderate signs of illness (80%), and 13.8% of cases have serious signs within 24-48 h with the following symptoms: shortness of breath; hypoxia < 300% and/or pulmonary infiltration > 50%; tachypnea > 30 breaths/min[11]. 6.1% of patients with critical infections also have septic shock, respiratory and multiple-organ failure[11,12]. Approximately 25% of hospitalized patients require intensive care unit (ICU) care, and 4.3% die[12].

GENDER AND RACE DURING COVID-19

It has been demonstrated that 51% of reported cases of COVID-19 are male patients. This may be due to the higher levels of estrogen in female COVID-19 patients which can reduce COVID-19 severity and mortality via the elevation in innate and humoral immunity[13-19]. Moreover, in vivo studies have demonstrated that there are higher levels of angiotensin-converting enzyme 2 (ACE2) expression in male kidneys than in female kidneys, which may explain the differences in the susceptibility and development of COVID-19 between male and female patients.

Whether ACE2 expression varies in the lungs of male and female COVID-19 patients, is still unclear[20,21]. Furthermore, preclinical trials have suggested that ACE2 expression may increase vulnerability to COVID-19 in pregnant patients[22,23].

In the same way, COVID-19 varies between different ethnic groups in terms of severity and mortality. During the COVID-19 pandemic, American, Hispanic, and African communities have displayed higher rates of infection and hospitalization in comparison to Caucasian communities[24]. These discrepancies may be due to the higher occurrence of heart diseases, hypertension, obesity, diabetes, and asthma in minority groups[24].

GASTROINTESTINAL SYMPTOMS AND COVID-19
GI manifestations in COVID-19 patients

Gastrointestinal symptoms including, nausea, anorexia, vomiting, diarrhea, and abdominal pain are common in COVID-19 patients (Table 1)[12,25-35]. In the SARS infection of 2002-2003, diarrhea was the main feature and appeared in 16%-73% of SARS patients mainly in the first week of infection[36]. Similarly, diarrhea is considered a common digestive sign in COVID-19 patients, with an incidence of 1.3%-29.3%. However, the criteria for the diagnosis of diarrhea may be different in various hospitals, and its prevalence varied in different studies[37].

Table 1 Incidence of common gastrointestinal symptoms in patients with severe acute respiratory syndrome coronavirus 2 infection.
Ref.
Patient number
Anorexia, nausea or vomiting, n (%)
Diarrhea, n (%)
Abdominal pain, n (%)
Kujawski et al[207], 202012Nausea: 3 (25)4 (33.3)2 (16.7)
Hajifathalian et al[44], 2020 1059Anorexia: 240 (22.7)234 (22.1)72 (6.8)
Nausea: 168 (15.3)
Vomiting: 91 (8.6)
Young et al[208], 202018NA3 (17)NA
Tabata et al[209], 2020104NA8 (9.6)NA
Wölfel et al[210], 20209NA2 (22)NA
Chen et al[26], 202099Nausea and vomiting: 1 (1)2 (2)NA
Xu et al[27], 202062NA3 (8)NA
Gritti et al[211], 202021NA5 (23.8)NA
COVID-19 National Incident Room Surveillance Team[212]295Nausea: 34 (11.5)48 (16.3)6 (1)
COVID-19 National Emergency response Center[213]28NA2 (7)1 (4)
Sierpiński et al[214], 20201942NA470 (24.2)NA
Wu et al[28], 202080Nausea and vomiting: 1 (1.25)1 (1.3)NA
Wang et al[12], 2020138Anorexia: 55 (39.9)14 (10.1)3 (2.2)
Nausea: 14 (10.1)
Shi et al[29], 202081Anorexia: 1 (1)3 (4)NA
Vomiting: 4 (5)
Yang et al[30], 202050Vomiting: 2 (4)NANA
Mo et al[31], 2020155Anorexia: 26 (31.7)7 (4.5)NA
Nausea: 3 (3.7)
Vomiting: 3 (3.7)
Qi et al[215], 2020267Anorexia: 46 (14.2)10 (3.7)NA
Nausea: 6 (2.2)
Wen et al[216], 2020417NA29 (7)NA
Dan et al[217], 2020305Anorexia: 101(50.2)146 (49.5)12 (6)
Nausea: 59 (29.4)
Vomiting: 3 (2)
Ma et al[218], 202081NA6(7.41)NA
Luo et al[41], 20201141Anorexia: NA68 (6)45 (3.9)
Nausea: 134 (11.7)
Vomiting: 119 (10.4)
Liu et al[219], 2020238Anorexia: 14 (9.2)14 (9.2)1 (0.7)
Nausea: 2 (1.3)
Vomiting: 3 (2)
Ai et al[220], 2020102Anorexia: NA15 (14.3)3 (2.9)
Nausea: 9 (8.8)
Vomiting: 2 (2)
Zhao et al[221], 202075NA7 (9.3)1 (1.3)
Li et al[222], 202083NA7 (8.4)7 (8.4)
Lin et al[223], 202095Anorexia: 17 (17.8)23 (24.2)2 (2.1)
Nausea: 17 (17.9)
Vomiting: 4 (4.2)
Cholankeril et al[224], 2020207Anorexia: NA22 (10.8)14 (7.1)
Nausea: 22 (10.8)
Vomiting: NA
Ferm et al[43], 2020892Anorexia: 105 (11.8)177 (19.8)70 (7.8)
Nausea: 148 (16.6)
Vomiting: 91 (10.2)
Redd et al[225], 2020318Anorexia: 110 (34.8)107 (33.7)46 (14.5)
Nausea: 84 (26.4)
Vomiting: 49 (15.4)
Kluytmans et al[226], 202086NA16 (18.6)5 (5.8)

Among 204 COVID-19 patients in Hubei China, only 99 (48.5%) had gastrointestinal signs as their chief complaint. These COVID-19 patients had a diversity of digestive symptoms, including abdominal pain (0.4%), anorexia (83.8%), diarrhea (29.3%), and vomiting (0.8%)[38]. A retrospective study conducted by Guan et al[39] reported that among 1099 COVID-19 patients from 552 centers across China, 5% of cases had nausea and vomiting, and 3.8% of cases had diarrhea. A further study indicated that 32.5% of COVID-19 patients had at least one gastrointestinal tract (GIT) symptom. These symptoms included diarrhea (37.8%), anorexia (56.7%), abdominal pain (10.4%), nausea (16.5%), and vomiting (7.9%)[40]. Additionally, Luo et al[41] documented that 16% of 1141 cases, had at least one GIT symptom including, anorexia (98%), nausea, vomiting (66%), diarrhea (37%), and abdominal pain (25%). Furthermore, a research study conducted by Jin et al[42], which was the first COVID-19 study outside Wuhan, reported that the incidence of GIT symptoms was 11.4%; diarrhea was the most common of these symptoms (8.14%)[42].

In New York, GIT symptoms have been identified in a single-center-case series, which included 892 cases. The most common symptom was diarrhea (19.8%), accompanied by nausea (16.6%), abdominal pain (7.8%), vomiting (10.2%), and anorexia (11.8%)[43]. An additional retrospective study conducted in New York showed that of 1059 COVID-19 patients, 22% had diarrhea, 6% had nausea, 19% had vomiting, and 7% had abdominal pain[44]. In addition to these studies, the pooled prevalence of GI symptoms was found to be 17.6 % in a meta-analysis of 60 studies involving 4243 cases in 6 countries The most frequent symptom was anorexia (26.8%), accompanied by diarrhea (12.5%), nausea/vomiting (10.2%) and stomach pain/discomfort (9.2%)[45].

Furthermore, Goyal et al[46] indicated that hyperlipidemia was found in 11.7% of patients affected by SARS-CoV-2 where 92 patients out of 756 with COVID-19, had elevated serum lipase levels, resulting in acute pancreatitis. Therefore, COVID-19 patients with hyperlipidemia have an approximately 3-fold higher risk of poor clinical outcomes, including the need for ICU admission, mechanical ventilation, and death[46].

The study by Gadiparthi et al[47] showed that the higher Glasgow Blatchford bleeding score was 7 and 11 in 2 of 3 patients on admission and represents a high risk of gastrointestinal bleeding (GIB) with a need for intervention of more than 50%. However, both young patients responded by carefully controlling hemodynamic parameters, levels of hematocrit or hemoglobin, transfusion of packed red blood cells as needed and medical therapy. Although GIB was resolved, two patients died due to respiratory failure[47].

Besides GIT symptoms, autopsies of COVID-19 patients showed that there are gross and microscopic changes in the GIT. Segmental dilation and stenosis of the small intestine, accompanied by mucosal shedding and necrosis was described at autopsy, whereas colitis, inflammatory infiltrates, and interstitial edema, were found on histopathology imaging[48,49]. Lui et al[50] have shown pneumatosis, intestinalis, pneumoperitoneum, ascites, and thickening bowel wall in addition to ileus on abdominal imaging. Therefore, abnormalities of the GIT can be obvious on imaging.

Based on these previous data, physicians must realize that the key characteristics of COVID-19 infection before respiratory symptoms may be digestive symptoms and, in rare instances may be the only COVID-19 symptoms to occur.

Mechanisms of GI injury during COVID-19

Direct infection of gastrointestinal cells: The entry of SARS-CoV-2 virus into host cells is the main part of cross-species transmission. All coronaviruses bind to receptors and mediate their entry via glycoprotein and spike proteins[51]. It has been recognized that ACE2 mainly contains receptors for SARS-CoV[52], and dipeptidyl peptidase 4, for MERS-CoV[53]. A plethora of studies has shown that the spike (S) protein of SARS-CoV-2 has a high host ACE2 affinity[54], and enters host cells via the ACE2 receptor[55] as shown in Figure 3.

Figure 3
Figure 3 Mechanism of gastrointestinal symptoms in patients with coronavirus disease 2019. (1) Gut-lung axis: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds with angiotensin-converting enzyme 2 (ACE2) to enter the lung, which leads to the accumulation of angiotensin II (ANG II) and the reduction of Angiotensin (1-7). ANG II combined with angiotensin 1 receptor stimulates cytokine release and causes an upsurge of C-C chemokine receptor type 9 (CCR9) CD4T cells. Chemokine (C-C motif) ligand 25 subsequently enhances the recruitment of CCR9 CD4T cells into the small intestine. The changing flora then stimulates the polarization of T helper 17 cells, and eventually, interleukin 17A induces the recruitment of neutrophils. Cytokines and intestinal bacteria also enter the lung through the bloodstream, further affecting lung inflammation; and (2) Gut-liver axis: SARS-CoV-2 binds with ACE2 to enter the intestine, prevents absorption of the B0AT1/ACE2 transport pathway, and then decreases the stimulation of mammalian target of rapamycin to diminish the expression of antimicrobial peptides which result in gastrointestinal tract symptoms or enhanced ANG II that leads to the upregulation of tissue factor VIII, Von Willebrand factor, and plasminogen activator inhibitor-1 expression by endothelial cells resulting in mesenteric thrombosis. The intestinal flora, through the portal vein, is transferred to the liver, where it binds to toll-like receptors resulting in hepatitis. Additionally, the liver, can transport metabolites to the intestine via the biliary tract,. COVID-19: Coronavirus disease 2019; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ACE2: Angiotensin-converting enzyme 2: ANG II: Angiotensin II; Ang1–7: Angiotensin (1-7); AT1R: Angiotensin 1 receptor; CCR9: C-C chemokine receptor type 9; CCL25: Chemokine (C-C motif) ligand 25; Th17: T helper 17; IL-17: Interleukin 17; PMNS: Polymorphonuclear neutrophils; B0AT1: Sodium-dependent neutral amino acid transporter; mTOR: Mammalian target of rapamycin; AMPs: Antimicrobial peptides; FVIII: Tissue factor VIII; VWF: Von Willebrand factor; PAI-1: Plasminogen activator inhibitor-1; TLR: Toll-like receptor.

In small intestine cells, ACE2 is usually located and strongly expressed in type II epithelial cells[56,57]. It is considered an important enzyme in the renin-angiotensin system (RAS)[58,59] and plays an essential role in controlling inflammation and diarrhea[60]. Moreover, its deficiency leads to the accumulation of angiotensin II (ANG II)[61]. Subsequent studies[12,62-64] have proven that SARS-CoV-2, in COVID-19 patients, may invade the GIT via ACE2 receptors, causing digestive symptoms. It is now well acknowledged that the significant upsurge of ANG II level in COVID-19 patients is the cause of progression and severity of the disease.

Although in the mouse colon, the knockdown of ACE2 by the virus leads to an upsurge of ANG II levels; ACE2 does not primarily act via the intestinal RAS system but controls the homeostasis of intestinal amino acids, gut microbes and the expression of antimicrobial peptides[65]. Mice with blocked ACE2, for example, have significantly inhibited serum tryptophan that is important to the body’s niacin synthesis[66], therefore, inadequate intake of tryptophan or niacin results in pellagra[65]. It is well-recognized that tryptophan is absorbed on the lumen surface of intestinal epithelial cells via the B0AT1/ACE2 transport route and induces the mammalian target of rapamycin, which controls the consequently appearance of antimicrobial peptides, thereby having a direct influence on components of intestinal flora[65]. Ultimately, more than 90% of pellagra patients will develop colitis[67]. Hence, it is considered that SARS-CoV-2 attachment to the ACE2 in the GIT lowers the critical receptor level, disrupting the absorption of tryptophan and ultimately destroying the steady-state of the gut flora, resulting in diarrhea.

Furthermore, He et al[68] demonstrated that the pathological results of autopsies on COVID-19 patients indicated that proinflammatory cytokines (PICs) such as tumor growth factor-β1, monocyte chemokine-1 (MCP-1), tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were highly expressed in ACE2-expressing cells. There is an absence of PICs in cells that do not express ACE2. Numerous PICs produce the cytokine storm, which finally leads to multiple organ failure. Besides, plasma IL-2, recombinant human interferon (IFN)-induced protein-10, MCP-1, macrophage inflammatory protein-1A, IL-7, granulocyte colony-stimulating factor, IL-10, and TNF-α levels in COVID-19 patients were higher than those in healthy people[25]. Dendritic cells and macrophages show low levels of IFN and high levels of PICs and chemokines in the early stage of SARS-CoV infection[69-71]. Later, there is a rise in cytokine and chemokine levels, which causes severe tissue damage due to the large number of inflammatory cells, such as neutrophils and monocytes. In the same manner, SARS-CoV-2 can induce cells expressing ACE2 to release inflammatory cytokines, leading to the cytokine storm and multiple organ failure[72]. Furthermore, cytokine storms can have an effect on immune cells; lymphocytosis is known to be a common sign in severe cases of COVID-19, with a significant decline in the number of B, CD8+ and CD4+T cells as well as natural killer cells, which leads to lymph node necrosis, spleen atrophy, hepatomegaly, renal hemorrhage, necrosis, and degeneration of neurons[73].

Thromboembolic complications are being increasingly documented in COVID-19[74]. Acute mesenteric ischemia (AMI) has been reported in severe COVID-19 patients in addition to deep venous thrombosis and pulmonary embolism[75]. It has been demonstrated that ANG II stimulates the expression of tissue factor VIII (FVIII), von Willebrand factor, and plasminogen activator inhibitor-1 by endothelial cells, resulting in a state of hypercoagulation[76,77]. Histology of the small intestine secondary to mesenteric thrombosis revealed a prominent endothelium of the submucosa with evidence of direct viral invasion of endothelial cells along with diffuse endothelial swelling with mononuclear cell infiltrate. It is understood that there is stimulation of alternate and lectin complement trajectories [C5b-9 (membrane attack complex), C4d, and mannose-binding protein-associated serine protease 2] that destroy endothelial cells[78]. SARS-CoV-2 infection also resulted in an elevation of ANG II levels and other prothrombotic proteins, which led to AMI[78-81].

Gastrointestinal damage caused by lung infection: Any change in intestinal flora constituents affects the respiratory tract, via the common mucous immune system. Reciprocally, any damage to the respiratory tract mainly affects the digestive tract via immune regulation. This effect is known as the “gut-lung axis”[82,83]. Furthermore, SARS-CoV-2 cannot be detected in the stools of COVID-19 patients with digestive symptoms and thus GIT symptoms may not be affected by the direct damage caused by SARS-CoV-2. The entry of CD4+ T cells is essential to immunity and chronic enteritis in the intestinal mucosa. It is known that C-C chemical receptor type 9 (CCR9) is an important chemical receptor for the introduction of CD4+T cells into small gut cells[84]. Wang et al[84] showed after viral infection, that CCR9+ CD4+ T lung derived cells were amplified. The small intestinal epithelium can include chemokine (C-C motif) ligand 25[85], which promotes the recruitment of CCR9+ CD4+ T cells into the small intestine[86], which leads to impairment of the gut’s immune system and to destruction of intestinal flora homeostasis. This, in turn, stimulates the polarization of T helper 17 (Th17) cells in the intestine, and recruitment of neutrophils due to the production of large amounts of IL-17A[87], causing diarrhea, intestinal immune damage, and other gastrointestinal symptoms. Inflammation in the intestine may lead to the entry of intestinal flora and cytokines into the lung through the bloodstream, which affects the lung immune system[88]. Additionally, bacterial imbalance and intestinal mucosal damage can affect the gut-liver axis. In the intestine, host metabolites are transported through the portal vein to the liver and affect the function of the liver. The liver releases bioactive contents and bile acids and transfers them into the intestines through the systemic circulation[89]. This may lead to liver dysfunction in COVID-19 patients, due to these abnormalities[90] (Figure 3).

Gastrointestinal symptoms caused by drug side effects: Diarrhea due to antibiotics is the most common unwanted side effect of antimicrobial agents, including cephalosporins, macrolides and β-lactams. A retrospective study, in China, demonstrated that 260 COVID-19 patients treated with macrolides, fluoroquinolones, and cephalosporins resulted in 24.2% of patients developing diarrhea[91]. Another study of 138 patients with SARS-CoV-2 found that 38% had diarrhea with a medium period of 3-7 d during treatment[92]. The abovementioned data indicate that the early use of large quantities of antimicrobial agents could be linked to symptoms of diarrhea during COVID-19. Similarly, the prevalence of diarrhea in patients treated with antiviral agents such as oseltamivir is about 55.2%[93]. Other antiviral agents which can cause diarrhea as an adverse effect during the management of COVID-19 include lopinavir, chloroquine phosphate, remdesivir, and Chinese patent medicines (e.g., lianhuaqingwen capsules)[94]. Additionally, treatment with broad-spectrum antibiotics is a major risk factor for Clostridium difficile infection, which is considered the primary reason for nosocomial diarrhea[95]. It is unclear whether the above-mentioned factors including, the use of antibiotics or antiviral agents and increased gut inflammation along with a decrease in mammalian target of rapamycin (mTOR) activity, and antimicrobial peptides, are partly responsible alone or in combination for causing diarrhea in patients infected with COVID-19 via alterations in the gut flora[96].

Proton pump inhibitors (PPIs) are mainly used as a therapy for patients with peptic ulcers and gastroesophageal reflux disease. By blocking the proton pump, PPIs decrease gastric acid released into the stomach. Although the decrease in stomach acid can be beneficial in patients with stomach diseases, it can make the gut more susceptible to COVID-19 infection[97-99]. SARS-CoV S protein was suggested to fuse with patients’ cells in neutral pH conditions. Additionally, Darnell et al[100] also established that highly acidic pH (1-3) and alkaline pH (12-14) may lead to inactivation of SARS-CoV, while, in the case of neutral pH, the virus remains stable[101]. Zhou et al[102] reported that, under the conditions of pH 1.0 and 2.0, SARS-CoV-2 was inactivated and unable to infect cells which was related to the pH in an empty stomach by creating viruses pseudotyped with SARS-CoV-2 S protein. In addition, the study by Ramachandran et al[103] found that prehospitalization PPI-exposed patients had worse clinical outcomes, involving mortality of COVID-19 patients, irrespective of the existence of cardiovascular diseases. A possible explanation for this is that secretions in the stomach are in the pH range 1.0 to 3.5, while the pH in the small and large bowels ranges from 7.5 to 8.0. SARS-CoV-2 can cause gastric acid to inactivate most virus particles. If a person has a long period of acid suppression with PPIs, the pH in the stomach decreases. SARS-CoV-2 can also have a higher rate of entry in the gut, which leads to viral infection.

COVID-19 and pre-existing digestive diseases

In general, the existence of comorbidities is associated with dramatically low outcomes in COVID-19 patients. This may cause consequences for the management of previous gastrointestinal patients[104]. Patients that have inflammatory bowel disease (IBD) and have been treated with immunosuppressive drugs are more at risk for regular and serious infections and may be more at risk for SARS-CoV-2 infection[105]. It was reported in the IBD registry in Wuhan that none of 318 patients (204 patients with ulcerative colitis and 114 patients with Crohn’s disease) had been infected with SARS-CoV-2 following precautions for COVID-19 control and prevention[106]. Thus, the use of biologics and immunosuppressants, diet therapy, deliberate postponement of elective and endoscopic surgery and provisions for personal safety are recommended[107].

Considerations and management of IBD medications during COVID-19 infection: It is currently not recommended that IBD patients stop immunosuppressant drugs[11]. This is because there is a risk of disease reactivation in patients who discontinue their treatment, leading to severe inflammation, surgery, increased risk of hospitalization, and infection[108,109]. Non-hormonal anti-inflammatory drug use should be prohibited as the adverse effects of viral respiratory infections have been associated with triggering the reactivation of IBD[110].

No evidence-based recommendations for immunosuppressed patients have been made by clinical parties. Table 2 shows the specific considerations for the treatment of IBD patients mainly based on specialist beliefs. These suggestions can be edited and updated as new evidence emerges[108,110]. Overall, the same therapies can be used by patients with moderate to serious Crohn’s disease or ulcerative colitis, regardless of COVID-19 infection[110]. IBD therapies can be restarted after 14 d for asymptomatic IBD patients with SARS-CoV-2 infection whose therapy has been stopped[110].

Table 2 Therapy-specific considerations for inflammatory bowel disease patients.
Drug
Effects
Aminosalicylate acid derivatives (5-ASA)No proof of increased risk of COVID-19 infection
Continue treatment even in the case of COVID-19 infection
CorticosteroidsTheir safety during COVID-19 infection is uncertain
They can be used at a low dose and for a short period to treat disease relapses
Discontinue as soon as possible
Ileo-cecal CD patients can be treated with Budesonide; IUC patients can be treated with Budesonide MMX
Immunomodulators (Thiopurines and Methotrexate)No proof of increased risk of COVID-19 infection
Accompanied by increased risk of other viral infection
Not recommended to start with monotherapy
Combination therapy with biologics should be maintained
Recommendations in stopping
Stable disease
Sustained reduction in the case of elderly patients and/or significant comorbidities
Symptom progression of COVID-19 infection
Anti-TNF therapyNo proof of increased risk of COVID-19 infection
Infusion and dose intervals should be maintained
Starting with monotherapy (adalimumab or certolizumab)
Stop in the case of developing symptoms of COVID-19
Anti-IL-12/23p40 therapy (Ustekinumab)No proof of increased risk of COVID-19 infection
Monotherapy is recommended
Stop in the case of developing symptoms of COVID-19
Anti-a4b7 integrin therapy (Vedolizumab)No proof of increased risk of COVID-19 infection
Monotherapy is recommended
Stop in the case of developing symptoms of COVID-19
Janus Kinase inhibitors (tofacitinib)Although there is no proof of increasing the risk of COVID-19 infection, it may inhibit the immune reaction against viral infections
Starting is not recommended
Therapy should be maintained without elevating the dose
Stop if symptoms of COVID-19 develop

It is noteworthy that IBD patients should discontinue immunosuppressant drugs until COVID-19 is resolved, and medications can be resumed after complete resolution of COVID-19 symptoms or after two negative polymerase chain reaction (PCR) tests[111].

IBD surgery in the context of the COVID-19 pandemic: The new strain of coronavirus has increased the risk of severe pulmonary infection and extended hospitalization for IBD patients waiting for surgery, which is critical for IBD immunosuppressed patients. A recent report in Wuhan, China, demonstrated that 34 patients who underwent elective surgical procedures during the COVID-19 incubation period, developed COVID-19 pneumonia after surgery; 44.1% of patients were admitted to the ICU, and 20.5% of patients died[112]. Therefore, the majority of physicians have recommended postponing both elective and endoscopic surgery to protect patients and healthcare personnel and to minimize the usage of healthcare services and use personal protection equipment[113,114]. Eventually, the ultimate goal is to ensure the safety of patients and health care workers.

COVID-19 and the fecal–oral transmission route

A number of articles have disclosed that SARS-CoV-2 RNA can be found in patients’ stool, suggesting that SARS-CoV-2 has the ability to be transmitted via the fecal-oral route[115-117]. It has been demonstrated that some COVID-19 patients had positive fecal but negative PCR tests[118]. Wang et al[117] revealed that of 153 (29%) patients with COVID-19, 44 showed positive stool virus. Moreover, Xiao et al[49] indicated that of 73 COVID-19 patients hospitalized in China, 39 (53.42%) showed SARS-CoV-2 RNA in stools[49]. Surprisingly, stool samples were positive in 17 (23.29%) patients but respiratory samples were negative and the period of positivity ranged from 1 to 12 d in stools. Xiao et al[49] demonstrated that infectious SARS-CoV-2 may be secreted from virus-infected gastrointestinal cells. Therefore, stool samples should be frequently tested using real-time-PCR and transmission-based precautions should be taken into consideration[119].

Furthermore, the probability of SARS-CoV-2 fecal-oral transmission has highlighted the importance of adequate hand hygiene, especially in certain areas. Strict measures must be taken to deal with the stools of COVID-19 patients and the sewage from hospitals. Therefore, patients with preexisting gastrointestinal diseases will be more worried when they are infected with SARS-CoV-2 in addition to potential fecal microbiota transplant donors.

Pharmacologic management of GI symptoms in COVID-19

Microecological preparation: The intestinal flora generates various vitamins, bile acids, immune factors, and fatty acids via the decomposition of food and participates in immune system regulation[120]. If there is dysfunction or damage in the intestinal flora and/or mucosa, the virus may further stimulate infection through this pathway. Other studies have stated that probiotics have the availability to manage diarrhea caused by rotavirus[121]. Also, lactic acid bacteria and Bifidobacteria can contribute to antiviral antibodies in the human body, accelerating virus removal. Therefore, probiotic treatments and/or antiviral drugs, and antibacterial drugs may enhance the symptoms of SARS-CoV-2 diarrhea. Regarding the diagnosis and treatment protocols of COVID-19 in China, the use of intestinal flora regulators is preferred to preserve the intestinal micro-environmental balance and avoid secondary bacterial infection[122].

ACE2 inhibitors: As previously mentioned, ACE2 binds SARS-CoV-2 in cells. Therefore, to avoid SARS-CoV-2 infection the interaction between the receptor connection domain (RBD) of the virus and ACE2 could be blocked. A number of studies have shown that ACE2 inhibitors can regulate bowel metabolism, innate immunity, secretion of antibacterial peptides, and intestinal microbial homeostasis[122]. It was experimentally confirmed that the ACE2 pathway in epithelial cells of the small intestine trigger mTOR via nutrient stimulation and/or the tryptophan-nicotinamide pathway, thus affecting the composition of intestinal flora, and decreasing GIT indications in mice[60]. Azathioprine is an immunosuppressive agent similar to chloroquine. A recent study evaluated azathioprine and found that it could be regarded as an ACE2 inhibitor[123]. Additionally, in vitro studies have shown that Vaccinia virus can be inhibited by azathioprine[124]. With regard to molecular immunity, azathioprine competitively binds to ACE2, using a single chain (ScFv) antibody fragment attached to ACE2 or SARS-CoV-2, via the RBD. Thus, the human recombinant ACE2 antibody Fc segment bound by the S protein works by inhibiting attachment of the virus to ACE2[55]. It has been documented that a combination of Chinese medicines (e.g., baicalin in the Chinese medicine Scutellaria baicalensis, scutellarin in Erigeron breviscapus, hesperetin in lime and orange peel, glycyrrhizin in liquorice, and nicotinamide in soybean) and ACE2 resulted in the prevention of SARS CoV-2 infection.

Diet and enteral nutrition: A number of COVID-19 patients have significant anorexia. To ensure effective therapy, the basic energy, absorption, enteral and peristalsis movement of the intestine, and normal function of GIT micro-organisms and mucosal immunity should be taken into account as well as the functioning of the GIT and patients’ nutrition[94]. Nutritional risk assessment should be performed in patients with serious COVID-19 and gastrointestinal symptoms[125]. Once the risk of enteral nutrition has been eliminated, enteral nutrition should immediately be restored. If the patient has a gastrointestinal disorder and cannot withstand enteral nutrition, parenteral nutrition should be supplemented with a sufficient supply of energy. Patients in poor condition can be given digestive enzymes[125]. A nasogastric tube can be used for enteral feeding in patients who have undergone mechanical ventilation and are unable to take food orally. A nasal jejunal tube can be inserted when patients are at high risk of reflux aspiration or cannot handle nasogastric tube feeding. Generally, the patient gastrointestinal tolerability should be estimated appropriately and the enteral nutrition program correspondingly adjusted.

LIVER AND COVID-19
Clinical manifestations and pathological changes in hepatic injury in patients with COVID-19

Hepatic injury is a frequent adverse event in both SARS-CoV and Middle East respiratory coronavirus-infected patients and is associated with the severity of disease[126]. A substantial systematic analysis of 11 studies assessing the liver laboratory parameters of 2541 patients with COVID-19 showed increased AST and/or ALT (25%), lactate dehydrogenase (20%), bilirubin (3%) and normal alkaline phosphatase (ALP)[127]. This may indicate minimal direct liver damage caused by ACE2 overexpression in cholangiocytes. A major published study of 5700 patients found that AST and ALT were increased in COVID-19 patients by 58.4% and 39.0%, respectively[128]. Cai et al[129] showed that in 41% of patients, gamma-glutamyl transferase (GGT) was increased more than 3 × ULN, while, another research study demonstrated that GGT was raised in severe cases, but without an elevation in ALP[126].

Data from a preprint meta-analysis involving 20 retrospective studies and 3428 COVID-19 patients showed that increased levels of COVID-19 were related to significant increases in the levels of ALT, AST, and bilirubin[130]. Recently, a plethora of studies reported increased serum ALT, AST, and GGT levels in severe compared with mild or non-severe COVID-19 patients[39,131]. A recent meta-analysis associated high marker admission levels with patient mortality[132]. Other studies have shown that the increase in these parameters resulted in a worse pulmonary computed tomography (CT) score[133], increased numbers of ICU patients[12] and longer hospital stays[134]. In patients who died due to COVID-19, the incidence of elevated liver parameters ranged from 58.06% to 78%[32,135].

According to a study conducted by Lei et al[132], AST was the first indicator to be considered high when patients were admitted to hospital and was correlated with the highest COVID-19 death rates. A recent study carried out by Guan et al[39], around 1100 Chinese patients reported elevated levels of serum AST and ALT of 18% and 26% in non-severe COVID-19 patients, respectively, compared with 56% and 28% in severe COVID-19 patients. Previous findings revealed the crucial role of immune-mediated systemic inflammation in liver dysfunction in patients with serious COVID-19[9]. Recently, Gordon et al[136] proposed that mitochondrial proteins may interact directly with the virus, providing a cause for the high level of AST in the liver profile[136]. Wang et al[137] also identified anomalies in liver enzymes, higher radiologic scores as well as a partial pressure differential between alveolar arterial oxygen, higher GGT, disease intensity, higher ferritin, lower CD4+ T and B cells and lower albumin. It is considered that total bilirubin, AST/ALT, and ALT/ALP ratios have helped to predict survival in cirrhotic COVID-19 patients[138]. Serum albumin levels were also markedly lower in patients who died of COVID-19[32]. The adverse path of COVID-19 patients has been shown to include elevated serum levels of IL-6, ferritin, procalcitonin, and C-reactive protein. In addition to reduced albumin content and platelet count, the parallel increase in the level of ferritin, ALT and IL-6 indicates a greater role for liver participation in COVID-19[32,134]. The CT imaging score for pulmonary lesions is known as a hepatic injury indicator. Therefore, patients must undergo careful monitoring of liver function in order to identify any liver insults at an early stage[133]. The incidence of hepatic abnormalities in COVID-19 patients are depicted in Table 3.

Table 3 Incidence of hepatic abnormalities in patients with severe acute respiratory syndrome coronavirus 2 infection.
Ref.
Patient number
ALT (U/L)
AST (U/L)
TB (mg/dL)
Zhou et al[32], 2020191↑59 (31%)NoneNA
Shu et al[227], 2021545↑41 (7.5%)↑35 (10.1%)↑189 (34.7%)
Huang et al[25], 202041NA↑15 (37%)NA
Huang et al[228], 2020364 (13.3%)18 (58%)↑4 (12.9%)
Chen et al[26], 202099↑28 (28%)↑35 (35%)↑18 (18%)
Ai et al[64], 2020102↑20 (19.6%)↑26 (25.5%)NA
Xu et al[27], 202062↑3 (3.75%)↑3 (3.75%)NA
Yang et al[3], 2020168↑9 (8%)↑18 (17.3%)↑7 (6.4%)
Wu et al[28], 202080↑3 (3.75%)↑3 (3.75%)NA
Yao et al[229], 202040↑21 (52.5%)↑16 (40%)
Xu et al[230], 2020355↑91 (25.6%)↑102 (28.7%)↑10 (25%)
Cai et al[231], 2020298↑39 (13.1%)↑25 (8.4%)↑66 (18.6)
Richardson et al[1], 20205700↑2176 (39.0%)↑3263 (58.4%)↑24 (8.1%)
NA
Fan et al[1], 202040↑27 (18.2%)↑32 (21.6%)↑9 (6.1%)
Guan et al[39], 2020355↑158 (21.3%)↑168 (22.2%)↑76 (10.5%)

Morphological findings regarding the interpretation and description of liver parenchymal changes accompanying COVID-19 are rare, and most are seen at autopsy. It is noteworthy that the first autopsy liver specimen examinations carried out by Xu et al[139] showed moderate microvesicular steatosis and both portal activity and mild lobular activity. SARS-CoV-2 infection or drug-related hepatic damage may result in this liver insult. These results matched with those of Liu et al[140]. Preliminary research, consisting of 49 patients with COVID-19, showed that the portal intrahepatic system was affected with acute (thrombotic and luminal ectasia) or chronic (fibrous thickening of the vascular wall) features and the intrahepatic blood vessels were abnormally configured. These findings indicated that the major trigger in the pathogenesis of COVID-19 hepatitis is considered endothelial damage or coagulation dysfunction[141]. Additionally, in patients with critical COVID-19 there were no signs of damage to bile ducts or histological changes in liver failure[140]. Several studies failed to identify viral inclusion bodies in liver tissue[139,142]. Furthermore, the study by Li and Xiao[143] demonstrated that cirrhosis and regeneration signs with macrovesicular steatosis and accumulation in hepatocytes, along with atypical lymphocytic infiltration in the portal tract, may occur due to COVID-19. In the portal triad and centrilobular zones, sinusoidal expansion dilatation in zone 3, mild lymphocytic infiltrations and patchy liver necrosis were also revealed.

Moreover, the study by Ramachandran et al[144] showed that in hospitalized COVID-19 patients, elevated aminotransferases were associated with higher mechanical oxygen concentrations but did not achieve statistical significance after inflammatory marker measurement. In addition, patients with elevated aminotransferases did not have higher rates of mortality or prolonged length of stay as shown in Table 4.

Table 4 Outcome of the patients with severe elevation of aminotransferases in coronavirus disease 2019.
Ref.
Outcome of patients
SARS-CoV-2 patients with hypertransaminasemia (n = 20)
COVID-19 patients without hypertransaminasemia (n = 125)
P value
Ramachandran et al[169], 2020Shock9 (45%)38 (30.4%)0.207
Mechanical ventilation10 (50%)30 (24%)0.028
Died10 (50%)46 (36.8%)0.324
Length of stay in days, median (IQR)7 (4.3, 10.3)7 (5, 10)0.78

In China, some patients recovering from extreme COVID-19 were confirmed to have experienced special manifestations including a darkened face and pigmentation during treatment. The key causes of a darkened face and pigmentation were multiple organ injury, in particular liver injury[145,146]. Abnormal hepatic function can easily lead to pigmentation via the following three pathways: (1) Liver dysfunction can prevent estrogen from being inactivated[147]. The rise in estrogen decreases thiamine inhibition of tyrosinase in vivo, thus increasing the transformation of tyrosine into melanin[148]; (2) Abnormal liver function can cause hypofunction of adrenocortical hormones. The liver does not metabolize melanocytic stimulatory hormone produced by the anterior pituitary gland, which causes greater melanin secretion[149]; and (3) Liver damage can cause bleaching of the face due to iron in the blood that provides the facial skin[150,151] (Figure 4).

Figure 4
Figure 4 Facial blackness and dull skin after coronavirus disease 2019 recovery. Three possible mechanisms are shown: (1) Iron in the damaged liver drains into blood vessels. Blood with high iron levels can lead to blackening of the face when it supplies the facial skin; (2) Estrogen cannot be metabolized in the damaged liver. Thus, elevated estrogen in the blood enhances the conversion of tyrosine to melanin; and (3) When liver function is impaired, adrenocortical function is hypoactive, and melanocyte-stimulating hormone increases resulting in an elevation in the secretion of melanin. SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; MSH: Melanocyte-stimulating hormone; COVID-19: Coronavirus disease 2019.
Mechanisms of liver injury during COVID-19

Direct damage: It is established that SARS-CoV-2 enters the host cells via its binding to ACE2 on the surface of the host cell by the S protein[152,153]. However, the expression of ACE2 levels in liver tissue was estimated to be approximately 0.31% and its expression in bile duct cells was 20 times higher than that in hepatocytes on the basis of single cell sequencing and animal model analysis[154]. Furthermore, elevated levels of γ-glutamyl transferase and alkaline phosphatase were observed in COVID-19 patients[155], and inconsistent with biliary epithelial cells injury, approximately 10% of COVID-19 patients have high levels of total bilirubin. Thus, suggesting that SARS-CoV-2 can bind to cholangiocytes expressing ACE2, resulting in their injury (Figure 5).

Figure 5
Figure 5 Mechanisms of liver injury in patients with coronavirus disease 2019. (1) Angiotensin-converting enzyme 2-mediated targeting of cholangiocytes; (2) Antibody-dependent enhancement of infection; (3) Systemic inflammatory response syndrome and cytokine storms; and (4) Drug-induced liver injury. SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ACE2: Angiotensin-converting enzyme 2; ADE: Antibody-dependent enhancement of infection; SIRS: Systemic inflammatory response syndrome; ARDS: Acute respiratory distress syndrome; IFN-γ: Interferon-γ; IL-6: Interleukin-6; IL-18: Interleukin-18; TNF-α; Tumor necrosis factor-α; ROS: Reactive oxygen species; ATP: Adenosine triphosphate.

Antibody-dependent enhancement: Antibody-dependent enhancement of infection (ADE) may arise in patients with SARS[156]. ADE indicates that the interplay between the virus-based antibody and the CR and/or FC receptor complements increases the ability of the virus to reach macrophages, granulocytes, and monocytes (Figure 5). The virus frequently replicates in the aforementioned cells, leading to an increase in virus production and worsening of infection. Previous findings have indicated that SARS-CoV antibodies activate ADE, triggering SARS-CoV in immune cells that do not have ACE2 expression or harm the immune system[157]. Whether ADE can help SARS-CoV-2 infect immune cells through a non-ACE2-dependent pathway and participate in SARS-CoV-2 hepatic injury is an issue of concern.

Systemic inflammatory response syndrome and cytokine storms: Research has revealed that the inflammatory cytokines, including endotoxin ILs, and TNF-α in SARS patients who have liver function impairment have significantly higher levels than patients with normal liver function. Therefore, systemic inflammatory response syndrome (SIRS) and cytokine storms are risk factors for liver impairment in SARS-CoV and in MERS-CoV infected patients[158-160]. Limited pathological findings have indicated that COVID-19 hepatocytes exhibit non-specific inflammatory modifications in patients with serious infection such as Kupffer-cell hyperplasia and moderate proliferation, hepatocyte swelling and steatosis and a limited number of lymphocytes. Furthermore, the amount of IL-2 and IL-6 in COVID-19 serum has been shown to be substantially increased and linked to the seriousness of the disease[4]. Moreover, cytokines secreted by Th1 and Th2 cells in the serum of COVID-19 patients, such as TNF, IL-6, IL-18, IL-4, and IL-10 were significantly intensified in pro-inflammatory cells (CCR4 + CCR6 + Th17)[25,30,139]. Following SARS-CoV-2 infection, a large number of immune cells activate and induce excessive cytokines, such as TNF-α, IFN-μ, IL-6, IL-8, etc., leading to SIRS, acute respiratory distress syndrome, and induction of ischemia, eventually, resulting in cell destruction and necrosis as shown in Figure 4. Not only does such a vicious cycle lead to lung injury but may also progress to multiple organ damage. These results suggest that cytokine inflammatory storms may be one of the essential routes of liver injury (Figure 5).

Ischemia and hypoxia reperfusion injury: COVID-19 patients have various degrees of hypoxia, as more than 40% of cases required oxygen supplementation[30]. Complications such as aspiration and multiple organ failure can cause hypoxia, ischemia and subsequent shock. The suppression of cell survival signal transduction and hepatocyte death may be caused by ischemia and hypoxia, ATP depletion in hepatocytes, lipid accumulation, and glycogen consumption (Figure 5). Furthermore, the respiratory distress syndrome can cause oxidative stress that increases the production of reactive oxygen species (ROS). The ROS and lipid peroxidation products can induce redox-sensitive transcription factors and then release various pro-inflammatory factors leading to liver damage. These changes can exaggerate the ischemia of hepatocytes, influence the excretion of toxic metabolites and eventually stimulate liver injury. Hypoxia is also one of the main causes of liver injury in patients with serious COVID-19[161].

Drug hepatotoxicity: In China, the occurrence of drug-induced hepatic damage including, traditional Chinese patent medicines[162,163], antitumor drugs, antibiotics, antimalarial drugs, and anti-tuberculosis drugs[164,165], is second only to fatty liver disease and viral hepatitis (alcoholic and nonalcoholic). Several COVID-19 patients have a fever and consequently, use antipyretic and analgesic drugs. Therefore, a drug overdose can cause hepatic damage.

Recently, this was observed with abidol, lopinavir, ritonavir and other antiviral medications used to control COVID-19. A recent study published in JCI[166] demonstrated that CAP3A4 plays a critical role of the side-effect and metabolic pathways of ritonavir which can generate electrophilic material, radical free oxygen that can be covalently linked with liver cells leading to lipid membrane peroxidation, membrane integrity disruption of the Ca2+-ATPase membrane, interruption of the internal and external Ca2+ homeostasis of the cells, and finally leading to death. Furthermore, an overdose of the combination of lopinavir and ritonavir can stimulate the hepatic endoplasmic reticulum stress cascade, induce inflammatory reactions, trigger hepatocyte apoptosis through the caspase mechanism, suppress hepatocyte growth, and aggravate liver damage by the production of oxidative stress[167,168]. Some scientists have assumed that SARS-CoV-2 replication can be effectively inhibited by human immunodeficiency virus (HIV) protease inhibitors; although Shen et al stated that the risk of liver damage is increased in patients receiving hormones and HIV protease inhibitors[169]. The incidence of liver damage due to different medicines varies. However, the prevalence of liver damage due to more drug types is increasing. The diagnosis of hepatic damage due to medication includes a combination of medical history and appropriate testing to rule out other liver disorders and to estimate the relationship between hepatic injury and suspected medications by causality.

COVID-19 and previously-existing liver disease

Due to the global spread of chronic liver disorders, correlations among patients presenting with hepatic illness and COVID-19 need to be examined. A preliminary analysis showed that 2%–11% of patients had hepatic disease and COVID-19[170]. In a study of 1099 COVID-19 patients, hepatitis B infection occurred in 23 (2.1%) patients. Serious cases of hepatitis B infection were more likely (2.4% vs 0.6%) than milder cases[39]. SARS patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection were more vulnerable to serious hepatitis, likely because viral replication was increased during SARS-CoV infection[171]. Older patients with COVID-19 and have other conditions such as diabetes, cardiovascular disease, hypertension, and nonalcoholic fatty liver disease, are more susceptible to liver injury.

Moreover, patients with liver cirrhosis may be more susceptible to infection due to their systemic disease[172], thus, preventing COVID-19 is extremely important. None of 111 patients with COVID-19 in Wuhan had decompensated cirrhosis due to preventive measures. In contrast to this, 17% of 101 patients with COVID-19 developed decompensated cirrhosis at other hospitals where preventive measures were not implemented[173]. Viral transmission could occur during liver transplantation from donor to recipient, as previously described in SARS infection[174]. Recently, Michaels and colleagues showed potential transplantation risks in COVID-19 recipients[175]. The Italian Transplant Authority is carrying out nasopharyngeal swabs to diagnose COVID-19 before donation, with the subsequent exclusion of positive donors[176].

COVID-19 in liver transplant recipients: The worldwide spread of COVID-19 raises additional challenges for organ transplants. Transplant recipients with preoperative decompensated organs and chronic illness tend to contract respiratory viruses. Liver transplant patients, who are exposed to more people, during their wait for transplantation, have an increased risk of cross-infection with COVID-19. Qin et al[177] confirmed COVID-19 hepatocellular carcinoma in a patient following liver transplantation. On the 11th day after hepatic transplantation, the patient was diagnosed with COVID-19 following a positive PCR-test, with multiple ground-glass opacities in the left lobes. Long-term immune treatment in transplantation recipients prevents allograft rejection but significantly reduces the ability to protect them against COVID-19 due to their compromised immune system. A systematic analysis of 15 studies involving 223 patients with confirmed COVID-19 showed that simultaneous diarrhea was more likely to be present in patients who had undergone liver transplantation. The higher mortality rates in elderly patients with dyspnea and diabetes were approximately 23% in COVID-19 patients[178]. However, the latest data still do not confirm susceptibility to COVID-19 in liver transplant patients. A number of cases in Italy have indicated that children receiving liver transplants were not at elevated risk of serious lung disease relative to the general population despite being immunocompromised[179]. Similarly, three COVID-19-related deaths observed by D’Antiga[179] at an Italian transplant center were long-term patients on a minimal immunosuppression regimen, rather than recently transplanted patients with complete immunosuppression. Furthermore, a large global observational study by Webb et al[180] showed that the risk of death in COVID-19 patients does not substantially increase following liver transplantation.

Pharmacologic management of liver injury in COVID-19

COVID-19 causes mainly transient and indirect liver injuries, which can be caused by hypoxia, systemic inflammatory reactions, and medication. Thus, hepatic damage should be treated by elimination of the basic etiology in the COVID-19 patients. Correction of hypoxia by oxygen supplementation or mechanical ventilation, renal replacement treatment for cytokine storm, and restoration of intravascular effectiveness can enhance liver injuries in the event of septic shock[181]. Also early identification and reduction in the dosage of drugs inducing hepatic damage is crucial. Hepatoprotective anti-inflammatory medicines including L-ornithine-L-aspartate can be used in extreme cases as an adjuvant treatment[182]. It is worth noting that therapeutic drugs may be hepatotoxic, especially in chronic liver disease (CLD) patients. Furthermore, patients treated with immunosuppressive agents should be closely monitored due to drug interactions. Recommendations for the management of CLD, AIH, and immunosuppressed patients during a pandemic are summarized in Tables 5, 6 and 7[183,184].

Table 5 Recommendations of the American Association for the Study of Liver Diseases, Asian Pacific Association for the Study of the Liver, and European Association for the Study of the Liver for management of liver disease during coronavirus disease 2019.

Selected recommendations
To limit nosocomial spread(1) Decrease in-person visits via other alternatives such as virtual platforms
(2) Symptom investigation before entering hospitals to identify COVID-19 patients
(3) Reduce staffing to essential staff only
(4) Reduce the frequency of screening and laboratory examinations
(5) Adhere to recommended PPE by HCW and patients
(6) Maintain proper social distancing in hospitals
(7) Postpone unnecessary or elective operations
Management of CLD patients with COVID-19(1) These patients should be admitted to hospital early
(2) Prioritization of COVID-19 testing for patients with cirrhosis, CLD patients taking immunosuppressive agents and acute decompensated patients
(3) Repeated LFTs are advisable
(4) Early registration in clinical trials as much as possible
(5) COVID-19 patients with NAFLD should be kept under supervision
(6) Screening of hepatitis B surface antigen should be taken into consideration
(7) Drug-induced liver injury should be monitored
(8) These patients can receive 2-3 g/d of acetaminophen, while limiting the use of NSAIDs when possible
(9) HBV prophylaxis should be considered before starting immunosuppressive agents
(10) Stopping Remdesivir in decompensated liver disease patients with ALT more than 5 times the upper limit of normal
Management of chronic viral hepatitis (HCV and HBV)(1) Despite COVID-19 status, treatment continuity of chronic HCV and HBV is recommended
(2) In the absence of flare, HBV treatment should be stopped
(3) For uninfected individuals, HCV and HBV treatment should be continued according to guidelines
Management of HCC(1) HCC treatment should be continued according to guidelines; however, it can be delayed if necessary
(2) In the case of COVID-19 patients, delaying elective transplants and resection surgery, and stopping immunotherapy are advisable
(3) Early admission to hospital is recommended for HCC patients
Management of pre- and post-transplant recipients(1) Screening donor and recipient for COVID-19 is suggested
(2) For donors testing positive for COVID-19, transplantation surgery should be postponed
(3) Prioritization of patients with short-term prognosis
(4) For post-transplant patients, a reduction in immunosuppressive dose can be considered for moderate COVID-19 cases, while for mild COVID-19 cases, the dose should not be reduced
(5) For post-transplant recipients, vaccination against pneumonia and influenza is advisable
Table 6 Recommendations of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver for the management of auto-immune hepatitis during coronavirus disease 2019.

Selected recommendations
Virtual platforms are recommended to minimize in-person visits as much as possible
COVID-19 testing is advised in cases of acute deterioration and liver failure
Patients with low risk of complications (patients on chronic immunosuppressive therapy)(1) Frequent patient-provider communications should be closely supervised; (2) Virtual platforms should be used to decrease contact; and (3) Ensure enough drug supply and refills to decrease running out of medications
Patients with moderate risk of complications (symptomatic disease without cirrhosis)(1) Empiric therapy via virtual healthcare platforms as much as possible; and (2) Preventing liver biopsy whenever possible
Patients with high risk of complications (acute flare, decompensated cirrhosis)(1) Reduce invasive procedures as much as possible; (2) In the case of COVID-19 patients, if lymphopenia develops, dose reduction of antimetabolites is recommended; and (3) In the case of infection, corticosteroids should be attenuated
Table 7 Recommendations of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver on the use of immunosuppressive therapies in chronic liver disease during coronavirus disease 2019.

Suggestions
(1) Starting with corticosteroids and immunomodulators should proceed; and (2) Risk benefit ratio assessments should be carried out
Patients on immunosuppressive treatment and not infected with COVID-19Decreases or adjustment of doses is not advisable
Patients infected with COVID-19 on immunosuppressive drugs(1) Reduce corticosteroids dose after specialist physician (consider tapering to prevent adrenal insufficiency); and (2) Decreasing the doses of cyclosporine, mycophenolate, and azathioprine is recommended in severe COVID-19 (especially patients with lymphopenia)
Patients requiring initiation of immunosuppressive agentsStarting treatment is suggested in these patients regardless of COVID-19 status
COVID-19 IN THE ENDOSCOPY UNIT

Although millions of people have remained at their houses to decrease the transmission of SARS-CoV-2, the risk of COVID-19 amongst health workers is high.

For example, the Chinese National Health Commission determined that approximately 3300 health workers were infected in early March[185]. It is well-known that endoscopic staff are at high risk of airborne droplet infection, conjunctiva contact and surface contact contamination[182,186]. Airway suction and other cough-induced procedures result in an increased risk of SARS-CoV-2 transmission[182]. It must be noted that the possible risk of exposure to feces removal is not confined to upper endoscopy[35].

A prospective study conducted by Johnston et al[187], revealed the quantification of unrecognized bacteria to endoscopists exposed to biological samples leading to infection transmission. In this investigation, 227 endoscopic face shields were examined for colony-forming units (CFUs), and 1-15 CFU, 91/227 (40%); 16-30 CFU, 6/227 (2.6%); 30 or more CFU, 6/227 (2.6%) significantly increased after endoscopy. Similarly, in 1999, a research study carried out by Mohandas and Gopalakrishnan[188] in a tertiary care hospital in India of 786 endoscopies (149 lower and 162 therapeutic endoscopies) concluded that the splash rate to the skin of the forearms, feet, and face was 9.5%, while the splash rate to the eyes was 4.1%.

The duodenoscope is the most complex medical equipment that undergoes disinfection after patient use[189]. Virus risk factors include non-compatibility with disinfection guidelines, the promotion of biofilm deposition because of its complicated nature, surface defects and infected automated endoscopes[190,191]. It is considered that endogenous infections due to the gut flora of patients are the most common infections after endoscopy[192]. Exogenous infections such as Escherichia coli (71%), Klebsiella (14%), and Enterobacter (5%) can occur due to contaminated scopes and may be avoided by thorough cleaning[192,193]. Currently, Pseudomonas aeruginosa is the most common organism isolated from contaminated endoscopes[194]. Other microorganisms include, Mycobacteria, Helicobacter pylori, Clostridium difficile, HBV and HCV[195]. Recently, studies on duodenoscopy-associated infections including multidrug-resistant organisms, particularly carbapenem-resistant Enterobacteriaceae, have surfaced[196]. Numerous infections occurred despite sufficient disinfection, indicating that professional and government bodies should provide additional recommendations for duodenoscope processing[197,198]. To date, The Food and Drug Administration and Centers for Disease Control and Prevention have recommended comprehensive cleaning followed by high-level disinfection for reprocessing of flexible GI endoscopes[199-201].

In COVID-19 patients single-use duodeno-scopes may be important. However, they are not accessible worldwide and have cost-related constraints[202]. Several societies have advocated the use of room negative pressure, particularly for COVID-19 patients, or if endoscopy is urgently needed[203]. Intraprocedural changes such as minimal verbal communication, avoiding procedures in patients with inadequate bowel preparation, and avoiding spillage of GI contents via the biopsy channel should be introduced[204]. A previous study reported the use of a “double gauze technique”; one for the endoscopists and the other for technicians in a controlled fashion to prevent the “whip” effect of accessories and spillage of GIT secretions[204] Institutional requirements for minimum staff involved in the procedure have been developed[205]. Thus, the risk of exposure among endoscopy personnel is diminished. Endoscopy techniques performed with moderate sedation without the need for anesthetic agents (endoscopy driven sedation) can also reduce the risk of transmission. However, in the case of procedures requiring general anesthesia, policymakers recently recommended the use of endotracheal intubation to diminish the risk of aerosolization due to suspected or confirmed COVID-19[206]. Other methods to avoid splashes include the use of regular precautions such as full-sleeve gowns and suitable footwear[187].

GAPS IN KNOWLEDGE

Although there is a theoretical risk of fecal-oral transmission of COVID-19, the actual risk of transmission is extremely low. Despite this risk, endoscopy units have been functioning and reopening with no significant outbreaks noted.

CONCLUSION

COVID-19 can lead to lead to acute respiratory infection, and a high rate of morbidity and mortality. The main signs of COVID-19 are respiratory system reactions, and gastro-intestinal symptoms are also very common. COVID-19 patients with GIT symptoms are more probably associated with severe complications such as ARDS and liver damage, with a poor prognosis. Hence, during diagnosis and treatment of the disease, GIT symptoms should be taken into consideration as well as virus transmission via the fecal-oral route. In addition, it is advisable to take care of patients with chronic liver disease and they should be treated with medications that are able to prevent inflammatory responses and protect liver functions during COVID-19. Furthermore, the harmful effects of some drugs on the gut and liver during hospitalization must be identified and evaluated frequently. Further studies on the intrinsic relationship between COVID-19, hepatology and gastroenterology are urgently required.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country/Territory of origin: Egypt

Peer-review report’s scientific quality classification

Grade A (Excellent): A, A

Grade B (Very good): B, B

Grade C (Good): C, C, C

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Grade E (Poor): 0

P-Reviewer: Perisetti A, Song B, Vij M, Watanabe T S-Editor: Fan JR L-Editor: Webster JR P-Editor: Yuan YY

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