Coronavirus disease 2019 gastrointestinal and liver manifestations in adults: A review

Abstract Coronavirus disease 2019 (COVID‐19) is an important health problem that has a serious adverse impact on the global economy and healthcare systems. The virus is not only involved in the respiratory system, but also causes other systemic effects as well as several gastrointestinal and liver issues. Evidence has shown direct viral invasion into the gastrointestinal tissue and supporting vascular network, causing various manifestations such as diarrhea, nausea, gastrointestinal bleeding, and abnormal liver function tests. The degree of gastrointestinal injury, especially in terms of liver involvement, is correlated with disease severity. There is no specific treatment for gastrointestinal involvement, and the symptoms can be managed with supportive therapy. Moreover, increased liver decompensation and mortality can be found in COVID‐19‐infected patients with coexisting liver disease. As the virus can be identified in gastrointestinal contents, endoscopic procedures during the pandemic should be carefully selected and proper protection strategies should be encouraged to prevent viral transmission.


Introduction
In December 2019, a group of patients in Wuhan, China, developed viral pneumonia caused by a newly identified β-coronavirus. 1-3 The virus was renamed, "severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)," and the disease that causes it is called coronavirus disease 2019 (COVID-19). 2,4 SARS-CoV-2 is an enveloped, single-stranded, positivesense RNA virus with a high transmission ability. 5,6 From the first outbreak on 30 January 2020, in China, COVID-19 was registered as the sixth Public Health Emergency of International Concern (PHEIC) by the World Health Organization which declared COVID-19 as a pandemic on 11 March 2020. 7,8 Later, SARS-CoV-2, spread all over the world, leading to more than 79.2 million cases and over 1.7 million deaths by the end of 2020. 9 Gastrointestinal symptoms in COVID-19 patients are common and have been reported to correlate with disease severity. 10 Moreover, the virus particles can be identified in the gastrointestinal luminal content, which suggests a relationship between the virus and the gastrointestinal tract. This review aims to provide information regarding the gastrointestinal and liver manifestations of COVID-19, as well as its management during pandemics. To achieve this, a search was made of English-language human studies listed in the PubMed database, EMBASE, and other research published between February 2020 and March 2021. The keywords gastrointestinal and liver were used alone or in combination with COVID-19. The references of the identified articles were also searched for potentially relevant studies, and systematic reviews, meta-analyses, and case reports of special techniques were included. Duplicated data or data published as abstracts in academic meetings were excluded.

Clinical course of SARS-CoV-2 infection
The mechanism by which a virus that originates in animals can spread to humans involves genetic alterations that enable it to infect and be transmitted from humans to humans. There is a similarity between SARS-CoV-2 and Bat-CoV-RaTG13 (a SARS-like betacoronavirus in bats), supposing that a bat might be an initial host and Manis pentadactyla (Chinese pangolin) as the intermediate host, while humans act as accidental hosts. Some studies have shown that pigs or pangolins might have been intermediate hosts and snakes are probably among the virus reservoirs for human infection. 11,12 The incubation period for COVID-19 is generally not greater than 14 days following exposure, with a median time of 5 days. 13,14 The infection is associated with five different clinical courses: Asymptomatic infection, mild to moderate cases, severe cases, critical cases, and death. 15,16 Although it is highly transmissible, more than 80% of infected patients have mild disease. 15,17 The remaining 20% have severe disease, and approximately 5% of patients exhibit critical illnesses such as respiratory arrest, septic shock, or multiple organ failure. 13,18 SARS-CoV-2 infection has an estimated 1-3% mortality rate due to the development of acute respiratory distress syndrome (ARDS), and uncontrolled immune stimulation, the so-called "cytokine storm." Risk factors associated with mortality include advanced age, obesity, diabetes, and hypertension. 19 Other complications of COVID-19 include cardiac and cardiovascular complications, arrhythmias, acute cardiac injury, and shock. Thromboembolic complications, including pulmonary embolism and acute stroke, as well as neurologic complications, including encephalopathy, have also been reported.

Mechanism of gastrointestinal involvement
SARS-CoV-2 uses the receptor angiotensin-converting enzyme 2 (ACE2) to enter cells in the human lower respiratory tract. This receptor is also abundant in gastrointestinal epithelial cells. 13,20,21 As a result, apart from nasopharyngeal swabs, SARS-CoV-2 particles can also be found in fecal samples, esophagus, stomach, duodenum, and rectum. 22,23 Evidence of COVID-19 infection in the gastrointestinal tract has also been discovered by isolating viral RNA from gastrointestinal epithelial cells and by intracellular staining of viral nucleocapsid proteins in the same cell. 24 The COVID-19 pathogen enters the gastrointestinal epithelial cells through binding of its spike (S) proteins to the cellular surface ACE2 receptors (Fig. 1). Following cell entry, the virus hijacks host cell organelles to produce viral RNA and proteins. Finally, the newly assembled virions are secreted from the infected cell into the intestinal lumen by exocytosis. 25 An intracellular interferon-mediated immune response triggered by SARS-CoV-2 infection and the activation of immune responses from lymphocytes and inflammatory cells, which infiltrated the lamina propria, leads to the release of cytokines such as interleukin 2, 6, 7, 10, tumor necrosis factor (ΤΝF) α and calprotectin. 26 These cytokines, in turn, mediate various effects on the gastrointestinal tract, 27 as shown in Figure 1.
The SARS-CoV-2 viral RNA can be detected in feces in almost half (48.1%) of the COVID-19 patients with gastrointestinal symptoms compared to approximately 9% of patients without gastrointestinal symptoms. 10 The viral shedding in stool can persist up to 33-47 days after the first onset of illness, which is even Figure 1 Schematic representation of the mechanism of coronavirus disease 2019 infection on the enterocytes and its effect with various part of gastrointestinal system. The virus adheres to the intestinal mucosa via angiotensin-converting enzyme 2 receptors and produce various cytokines as well as chemoattractant proteins and inflammation proteins that cause injuries to various organ in gastrointestinal system (adapted from reference [27] ).

COVID-19 Gastrointestinal and Liver Manifestations
A Sirinawasatien et al.
longer than the clearance of the virus from the respiratory tract. 6,28- 30 The prolonged duration of viral shedding through fecal material suggests the importance of preventive measures against fecal contamination. There have been numerous reported cases of diagnosed COVID-19 patients presenting with gastrointestinal manifestations, such as diarrhea, nausea, vomiting, and abdominal pain. The prevalence of GI symptoms varies greatly, ranging from 2 to 57%. [31][32][33] In addition, many cases have been reported of abnormal liver chemistry during disease progression and higher rates of liver dysfunction have been found in patients with severe disease. [34][35][36][37][38][39][40][41] Gastrointestinal manifestation The symptoms of patients infected with SARS-CoV-2 are summarized in Figure 2. 19 Several studies from different countries have reported a wide range of gastrointestinal symptoms (Table 1). 2,42 Also, these patients with gastrointestinal symptoms seem to require longer periods of hospitalization. [35][36][37]43 In contrast, the time from gastrointestinal symptoms to hospital presentation was 9 days, compared with 7.3 days for patients with respiratory symptoms. 13 Gastrointestinal symptoms can be found ranged from 1.1 to 49.5% of COVID-19 patients according to different studies. The most common symptoms are diarrhea (2-49.5%), anorexia (26.8%), nausea and or vomiting (3.9-10.2%), and abdominal pain (1.1-9.2%). 2,10,42,44,45 Gastrointestinal symptoms usually worsen with disease progression and are correlated with a more insidious onset of disease. 2,33 There have also been reports of acute hemorrhagic colitis presenting with gastrointestinal bleeding. 2,30,33,42 Interestingly, in a meta-analysis, the occurrence of gastrointestinal bleeding was found to be associated with increased mortality. 46 Apart from the luminal involvement itself, endothelialitis and microthrombi with evidence of SARS-CoV-2 viral particle deposition have been reported in COVID-19 patients presenting with respiratory failure, and nonocclusive mesenteric ischemia has been found in those who underwent colectomy. 47,48 These findings could be explained by the expression of ACE2 on intestinal enterocytes, which makes both the small and large intestines susceptible to SARS-CoV-2 infections. 24,44,49,50 Another organ that has been attacked by SARS-CoV-2 is the pancreas. 13 A recent study by Wang et al. of 52 patients with COVID-19 pneumonia revealed that 17% experienced pancreatic injury, which was defined as elevated amylase or lipase. 51 Mechanisms by which pancreatic injury could occur include direct cytopathic effects of SARS-CoV-2, or indirect systemic inflammatory and immune-mediated cellular responses, leading to organ damage or secondary enzyme abnormalities. Abundant amounts of ACE2 receptors are found in pancreatic islet cells, indicating that SARS-CoV-2 may also bind to ACE2 receptors in the pancreas and cause pancreatic injury. 52

Management of gastrointestinal involvements
Gastrointestinal symptoms such as nausea and vomiting can be treated with antiemetic medication; however, before initiating supportive care, further investigation is recommended to rule out infectious causes such as Clostridium difficile infection. The use of antibiotics remains controversial and is recommended only Figure 2 Systemic manifestations of coronavirus disease 2019 (adapted from reference [19] ). when a coinfection is noticed. Patients should be informed about hand hygiene and the importance of maintaining social distancing. 42 Due to evidence of SARS-CoV-2 involving the gastrointestinal tract, many therapies and interventions for gastrointestinal diseases need to be adapted to reduce the spread of the virus through luminal content during the pandemic. There are several concerns and the recommended guidelines for endoscopic procedures, fecal transplantation, and management in patients with inflammatory bowel disease.
Gastrointestinal endoscopy. As gastrointestinal endoscopy is considered to be an aerosol-generating procedure, 53   4. Patients taking vedolizumab should stop therapy. 5. Patients on ustekinumab should stop therapy. 6. Patients taking prednisone ≥20 g/day should stop or taper the doses if possible. 7. Thiopurines (6-mercaptopurine, azathioprine), methotrexate, and tofacitinib also tend to inhibit the body's immune response to viral infections; as a result, they should be stopped.
The above mentioned IBD medications can be restarted after patients recover from COVID-19. 15

Liver manifestation of COVID-19
Abnormal liver function is common in patients with COVID-19. Aspartate transaminase (AST) or alanine transaminase (ALT) elevation has been reported in up to 13-58% of patients, while bilirubin elevation can be seen in 11-23% of patients, and less frequently, alkaline phosphatase (ALP) elevation in 5-10%, and gamma-glutamyl transferase (GGT) elevation in 13-54% of patients. 35,36,[57][58][59][60][61][62][63][64][65] The pattern of liver injury is mostly hepatocellular rather than cholestatic and usually mild. 66 Liver test abnormalities are more frequent in patients with more severe COVID-19, and their severity correlates with the outcome of COVID-19. 67 68 Another study also demonstrated that 76.3% of patients with COVID-19 (n = 417) had abnormal liver tests in hospital while 21.5% had "liver injury" defined as ALT and/or AST >3 Â the upper limit of normal (ULN) or ALP, GGT, and/or total bilirubin >2 Â ULN. 62 AST is more frequently elevated than ALT and is associated with COVID-19 severity and mortality, which might reflect immune-mediated inflammation or other nonhepatic causes. 37,[69][70][71] The presence of abnormal liver tests and liver injury was associated with progression to severe pneumonia, and the use of lopinavir/ritonavir was also found to increase the odds of liver injury by 4-fold. 62 In addition, low serum albumin levels on hospital admission were found to correlate with COVID-19 severity. 69,70,72 The possible pathogenesis of hepatic manifestation is believed to be multifactorial, including direct cytopathic effect of the virus, which may be related to the ACE2 receptor in the liver, hyper-inflammatory cytokine and cytokine storm from immune responses, hypoxic-ischemic liver injury, drug-induced liver injury, or coexisting with underlying liver diseases (e.g. chronic viral hepatitis, nonalcoholic fatty liver disease [NAFLD], cirrhosis).
In summary, COVID-19 causes a wide spectrum of gastrointestinal and liver involvement, ranging from direct invasion of the organism to the result of systemic immune processes. Gastrointestinal symptoms and liver function abnormalities are common during COVID-19 infection and may reflect disease severity. The possibility of viral transmission through gastrointestinal content should be considered, and protection against infected luminal content and aerosol-generated procedures during endoscopy should be emphasized. In addition, in patients with cirrhosis, COVID-19 infection is associated with an increased risk of liver decompensation and increased mortality.