Gastrointestinal and Hepatic Manifestations of Coronavirus (COVID-19)

Etiology

Coronaviruses are enveloped positive-sense single-stranded ribonucleic acid viruses. Based on their genomic structure, they are classified into 4 different categories as follows: 

• Alphacoronavirus 
• Betacoronavirus 
• Gammacoronavirus 
• Deltacoronavirus [6]

SARS-CoV-2 is a betacoronavirus belonging to the same subgenus as the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus, which have been previously implicated in epidemics with mortality rates up to 10% and 35%, respectively. Genomic characterization of the 2019 novel coronavirus demonstrated 89% nucleotide identity with bat SARS-like CoV and 82% with human SARS-CoV.[7] Throughout the COVID-19 pandemic, SARS-CoV-2 has undergone frequent mutations, resulting in new viral variants. The GI tract and the liver were frequently involved in both the SARS-CoV and MERS-CoV outbreaks, with symptoms similar to those reported with SARS-CoV-2.

Epidemiology

Since the first reported cases of COVID-19 from Wuhan, China, in December 2019 and the subsequent declaration of COVID-19 as a global pandemic by the World Health Organization, this highly contagious infectious disease has spread to more than 200 countries so far, with more than 701 million cases, and more than 6.9 million deaths reported globally. Patients aged older than 65 and patients with specific underlying medical comorbidities (eg, severe obesity, hypertension, chronic kidney disease, diabetes, chronic lung disease, positive smoking status, use of chronic immunosuppressants) are at increased risk of developing severe COVID-19 infection. Based on the results of a meta-analysis of 50 studies from the United States and the United Kingdom, it was noted that patients of Black and Asian ethnic minority groups were at increased risk of contracting COVID-19 infection compared to White patients. In addition, Asian patients may be at increased risk of intensive care unit admission and death, which has significant global public health implications.[8]

Pathophysiology

Effect of SARS-CoV-2 on the Gastrointestinal Tract

The pathogenesis of GI tract involvement in SARS-CoV-2 is likely multifactorial. Several hypotheses have been described, including direct angiotensin-converting enzyme 2-mediated viral cytotoxicity of the intestinal mucosa, cytokine-induced inflammation, gut dysbiosis, and vascular abnormalities. SARS-CoV-2 gains entry into the host cells by binding the SARS-CoV-2 spike protein to the angiotensin-converting enzyme 2 (ACE2) receptors present on the respiratory epithelium, followed by priming of the spike protein by the host transmembrane serine protease 2 that facilitates cell entry and subsequent viral replication.[9] The ACE2 receptor is abundantly expressed in enterocytes of the GI tract, primarily in epithelial cells, and human organoid models have demonstrated active viral replication.[10][11] 

SARS-CoV-2 was detected in endoscopic biopsy specimens of the esophagus, stomach, duodenum, and rectum from several patients.[12] Given the reported propensity of SARS-CoV-2 to spread via the fecal-oral route, many studies have reported evidence of cytokine-induced inflammatory response of the intestinal mucosa in patients with COVID-19, characterized by elevation of fecal calprotectin, a calcium- and zinc-binding protein which has been studied extensively as a marker of intestinal mucosal damage in inflammatory bowel disease.[13][14] Several studies have also hypothesized that intestinal infection with SARS-CoV-2 alters the fecal microbiota, potentially damaging enterocytes and causing diarrhea.[15] A study evaluating the effect of SARS-CoV-2 on the GI tract and gut microbiome reported increased infective competence and alteration of the gut microbiome in patients diagnosed with COVID-19.[16] Recent studies have highlighted the oral cavity's role as a portal for viral entry and replication (see Image. Mechanisms of Gastrointestinal Injury With COVID-19).[17] 

Effect of SARS-CoV-2 on the Liver and Pancreatobiliary System

Elevations in liver biochemistries are frequently observed in 14% to 53% of patients with COVID-19 infection.[18] The severity of the liver injury depends on the severity of the illness, with hepatic dysfunction occurring more frequently in patients with severe COVID-19 illness. Viral hepatitis classically manifests with a hepatocellular injury that is alanine transaminase predominant; however, hepatocellular injury in patients with COVID-19 infection appears to be aspartate aminotransferase predominant.[19] Because ACE2 receptors are expressed in cholangiocytes, mild elevations in alkaline phosphatase and gamma-glutamyl transferase are not uncommon in patients with COVID-19.[20]

The pathogenesis of liver injury is likely multifactorial and is explained by various hypotheses, including ACE2-mediated viral replication in the liver and its resulting cytotoxicity, hypoxic or ischemic injury, immune-mediated inflammatory response, drug-induced liver injury, and worsening of preexisting liver disease.[21] Severe cytokine-induced systemic inflammation and associated hemodynamic compromise could also contribute to the abnormal liver functions noted in patients with severe COVID-19 infection. Liver enzyme abnormalities can also be attributed to drug-induced liver injury secondary to newer antiviral agents such as remdesivir or concurrent medication use with hepatotoxic potential.

The role of preexisting liver disease in the pathogenesis of COVID-19-associated liver injury is not well studied. Based on data from 2 international registries involving 745 patients with chronic liver disease (with and without cirrhosis) and COVID-19 infection, the mortality rate was significantly higher in patients with cirrhosis at 32% compared to 8% in patients without cirrhosis. Moreover, mortality rates differed by underlying Child-Pugh Class (CPC) score: 19% in CPC A, 25% in CPC B, and 51% in CPC C.[22] Patients with chronic liver disease diagnosed with COVID-19 are at an increased risk of poor clinical outcomes.[22][23][24]

In addition to luminal GI tract cells, ACE2 is expressed in pancreatic islet cells and in pericytes of the pancreatic microvasculature. Literature describing the effect of SARS-CoV-2 on the pancreas, manifesting as acute pancreatitis, is limited. Hyperlipasemia has been reported in a minority of COVID-19 patients, but it is not specific to pancreatitis and does not reflect severe infection or poor clinical outcome.[25][26] However, a single-center prospective clinicopathologic case series reported focal pancreatitis with necrosis of the pancreatic parenchyma and adjacent adipose tissue, as well as calcifications, in 4 patients.[27] 

Prothrombotic State

ACE2 binding to SARS-CoV-2 is thought to cause endothelial damage, thereby promoting inflammation and hypercoagulation. There is likely a complex interplay among endothelial damage, proinflammatory cytokines, and underlying coagulopathy caused by sepsis/severe disease. This can cause a hypercoagulable state, leading to conditions such as mesenteric ischemia or portal vein thrombosis, as well as microvascular thrombi in the GI and other systems.[4]

Histopathology

Histopathology Examination of the Gastrointestinal Tract

Histopathological examination of the endoscopic specimens demonstrates positive staining of the viral nucleocapsid protein in the gastric, duodenal, and rectal epithelium cytoplasm. Numerous infiltrating plasma cells and lymphocytes with interstitial edema were seen in the lamina propria of the stomach, duodenum, and rectum. Histopathological examination of the small bowel in a patient admitted with mesenteric ischemia suggested prominent endothelial inflammation of the submucosal vessels and apoptotic bodies.[28]

Histopathology Examination of the Liver 

Post-mortem histopathological examination of liver tissue in a deceased patient with COVID-19 infection demonstrated nonspecific findings of moderate macrovesicular steatosis without any intracytoplasmic or intranuclear inclusions commonly associated with underlying nonalcoholic fatty liver disease, sepsis, or secondary to drug-induced liver injury.[29] A prospective single-center clinicopathologic case series study involving the post-mortem histopathological exam of major organs of 11 deceased patients with COVID-19 (mean age 81 years) reported findings of hepatic steatosis in all patients. The liver specimens of 73% of patients demonstrated chronic congestion. Different forms of hepatocyte necrosis were noted in 4 patients. Seventy percent of patients demonstrated nodular proliferation.[27]

History and Physical

Treating clinicians must obtain a detailed clinical history of the onset and duration of symptoms, travel history, exposure to individuals with COVID-19, underlying comorbidities, and medication history. Patients with typical clinical signs suspicious of COVID-19, such as fever, cough, sore throat, loss of taste or smell, malaise, and myalgias, should be tested for SARS-CoV-2. Patients presenting with isolated GI symptoms such as diarrhea, nausea, vomiting, and abdominal pain, or with incidental findings of elevated serum transaminases, should also be tested for SARS-CoV-2 in a high COVID-19-prevalence setting.[30] Patients with SARS-CoV-2 infection can experience many clinical manifestations ranging from no symptoms to critical illness associated with respiratory failure, septic shock, or multiple organ failure.

Most patients present with clinical symptoms such as fever, cough, sore throat, shortness of breath, anosmia, dysgeusia, malaise, and myalgia. However, COVID-19 can present with GI manifestations alone or concur with the other symptoms described earlier. In a meta-analysis of 1992 patients, 1052 (53%) experienced GI symptoms, with diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%) being the most commonly reported.[31] Loss of appetite is also a commonly reported symptom in patients with COVID-19. A case report described the incidence of hemorrhagic colitis demonstrated endoscopically and was attributed to SARS-CoV-2 after all other etiologies, including ischemic injury, were ruled out.[32] 

Evaluation

Initial laboratory assessment should include a complete blood count, a comprehensive metabolic panel with renal and liver function testing, a coagulation panel, and serum lipase at presentation. Viral ribonucleic acid can be isolated from stool specimens of COVID-19 patients, as evidenced by results of a meta-analysis of 23 published and 6 preprint studies involving 4805 patients; fecal tests were positive for SARS-CoV-2 in 8 studies, and viral ribonucleic acid shedding was detected in 41% of patients, implying transmission of SARS-CoV-2 via the possible fecal-oral route, in addition to respiratory droplet transmission.[33]

COVID-19 is also frequently associated with elevations in liver biochemistries in 14% to 53% of patients.[18] Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are generally elevated 1 to 2 times the upper limit of normal, with normal to mildly elevated total bilirubin. Hepatic dysfunction occurs more frequently in severe COVID-19 illness compared to patients with mild illness. Patients with liver injury at presentation had a considerably higher risk of intensive care unit admission and death.[20][31] 

Due to the expression of ACE2 receptors in the cholangiocytes, it is not uncommon to see a mild elevation of alkaline phosphatase and gamma-glutamyl transferase in patients with COVID-19.[20] Infectious etiologies, particularly Clostridium difficile and other viral and bacterial enteric infections, should be excluded in patients presenting with isolated symptoms of acute diarrhea and abdominal pain.[34] A troponin level and an electrocardiogram should be performed to rule out cardiac injury, especially in patients with liver abnormalities, with AST significantly greater than ALT. Measuring inflammatory markers such as C-reactive protein, calprotectin, D-dimer, and ferritin can also be considered. 

Patients with COVID-19 and elevated liver biochemistries should be evaluated for etiologies unrelated to COVID-19, which must include checking a comprehensive hepatitis panel to rule out other viruses such as hepatitis A, B, and C.[35] In patients with autoimmune hepatitis (AIH) and orthotopic liver transplant (OLT) recipients with active COVID-19, disease flare or acute cellular rejection should not be presumed without a biopsy confirmation indicating the same.[34] Patients with COVID-19 are also increasingly being recognized as being at risk of developing prothrombotic complications, manifesting as acute mesenteric ischemia and portal vein thrombosis.[36].This is likely attributed to a hypercoagulable state associated with this viral illness. If clinically indicated, initial imaging may include a chest x-ray, ultrasound, computerized tomography, or magnetic resonance imaging/magnetic resonance cholangiopancreatography. Endoscopic evaluation should be considered when clinically indicated, with appropriate personal protective equipment as recommended by the American Society for Gastrointestinal Endoscopy, given that endoscopy procedures are associated with a high risk of viral transmission.

Treatment / Management

Managing COVID-19 depends on the severity of illness at presentation, and patients should be appropriately triaged based on clinical symptoms. Asymptomatic patients or patients with mild illness can be managed in the ambulatory setting with supportive care and self-quarantine recommendations. However, patients with moderate-to-severe illness or patients at risk of developing severe illness should be clinically monitored in the hospital setting and managed as outlined in the updated National Institute of Health guidelines. As with other viral enteric infections, GI symptoms such as nausea and vomiting should be managed conservatively with intravenous fluids, antiemetic medications, and close monitoring of serum electrolytes.

Remdesivir is the first Food and Drug Administration-approved drug that has been indicated for use in adults and pediatric patients to treat hospitalized patients with COVID-19. Liver biochemistries must be performed at baseline and regularly monitored during initiation of remdesivir and throughout treatment. Potential hepatotoxic agents must be identified early and, if possible, avoided in patients with elevated liver biochemistries.

Nirmatrelvir/ritonavir (Paxlovid) was approved in December 2021 for use in patients with mild-to-moderate COVID-19 symptoms who are at high risk of complications from COVID-19. Nirmatrelvir is an antiviral that prevents intracellular replication of SARS-CoV-2, and ritonavir inhibits cytochrome P450 3A to increase nirmatrelvir concentrations. This medication is most effective when given within the first 5 days of symptom onset. See StatPearls' companion reference, "Nirmatrelvir-ritonavir," for more information. 

Patients with COVID-19 are associated with a hypercoagulable state, which puts them at risk of developing prothrombotic complications such as arterial and venous thrombosis. Clinicians should maintain a high index of suspicion for these complications and consider initiating appropriate systemic anticoagulation, provided there are no other contraindications to its initiation. Given that SARS-CoV-2 is an airborne pathogen, the aerosol-generating nature of endoscopy, and the potential for fecal-oral transmission, gastroenterologists, medical staff, and endoscopy staff are at increased risk of contracting or transmitting the virus. Implementing the precautions described below can prevent or reduce viral transmission.[37]

 Precautions Against COVID-19 in the Endoscopy Suite

• Because endoscopy is an aerosol-generating procedure, all endoscopists, endoscopy staff, and anesthesia providers must wear full personal protective equipment (PPE): gowns, National Institute for Occupational Safety and Health (NIOSH)-approved N95 masks, and face shields for all endoscopies, and, preferably, a powered air-purifying respirator for positive COVID-19 cases.
• All endoscopies must be performed in negative-pressure rooms if available.
• All endoscopy unit staff must be trained in PPE donning/doffing and in the proper storage of PPE equipment. 
• Placement of NIOSH-approved air filters in endoscopy rooms should be considered if possible.
• Before and after examination, frequent handwashing with soap and water for at least 20 seconds must be performed.

Differential Diagnosis

Although the GI symptoms are well-defined in patients with active COVID-19 infection, clinicians evaluating the patient must rule out other common etiologies of GI tract and liver disorders, including the following:

• GI tract etiologies that can cause similar symptoms include infectious diarrhea, ischemic colitis, inflammatory bowel disease, irritable bowel syndrome, small-bowel intestinal overgrowth, acute pancreatitis, chronic pancreatitis, acute cholecystitis, choledocholithiasis, and peptic ulcer disease. 
• Hepatic etiologies that can cause elevated liver enzymes include acetaminophen toxicity, viral hepatitis (A, B, and C), drug-induced liver injury, ischemic hepatitis, primary biliary cholangitis, Budd-Chiari syndrome, sepsis-related hypotension, autoimmune hepatitis, cytomegalovirus, Epstein-Barr virus, or herpes simplex virus infections, and muscle-related disorders, such as polymyositis or rhabdomyolysis.

Prognosis

The prognosis of COVID-19 largely depends on various factors, including the severity of illness at presentation, associated comorbidities, and treatment response. Based on a large cohort study from China involving 44,415 patients, most (81%) were diagnosed with mild illness and had a favorable clinical course. The other 19% were diagnosed with severe to critical illness requiring hospitalization, of which 5% developed critical illness characterized by respiratory failure and multiorgan dysfunction.[38] 

Many studies have reported that patients with COVID-19 infection who presented with primary GI-related symptoms or concurrent symptoms were at increased risk of hospitalization compared to those without GI symptoms.[1][2][3] However, this has not been comprehensively assessed, and more studies are needed. Acute liver failure is uncommon in patients with COVID-19. However, COVID-19 patients with liver injury on presentation are at significantly higher risk of admission to the intensive care unit and death.[20][31]

Complications

Considering the involvement of many major organ systems, COVID-19 can be regarded as a systemic viral illness. The complications of COVID-19 are likely due to progressive or sudden clinical deterioration leading to acute respiratory failure, acute respiratory distress syndrome, and multiorgan failure. Patients with COVID-19 illness are also increasingly being recognized as at risk of developing prothrombotic complications. Acute mesenteric ischemia is a life-threatening abdominal emergency associated with poor clinical outcomes.[36] 

Results from a study found bowel wall abnormalities in 31% of abdominal computed tomography scans (mostly in patients in the intensive care unit), including pneumatosis and portal venous gas. Laparotomy and pathology confirmed small bowel ischemia in some of these patients, which was thought to be due to small vessel thrombosis.[4] These prothrombotic complications are likely attributable to the hypercoagulable state associated with this viral illness. Other complications, such as severe hepatitis, hemorrhagic colitis, and pancreatic necrosis, could be multifactorial in the setting of hypoxia, cytokine-induced inflammation, and hypoperfusion.[27][32]