Gastrointestinal and Hepatic Manifestations of Coronavirus (COVID-19)

Etiology

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

• Alphacoronavirus (αCoV)
• Betacoronavirus (βCoV)
• Gammacoronavirus (γCoV)
• Deltacoronavirus (δCoV) [6]

SARS-CoV-2 is a Βetacoronavirus belonging to the same subgenus as the severe acute respiratory syndrome coronavirus (SARS-CoV) and the Middle East Respiratory Syndrome Coronavirus (MERS-CoV), 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, the SARS-CoV-2 virus has undergone constant mutations, leading to new viral variants. The GI tract and the liver were frequently involved in both the SARS-CoV and MERS-CoV outbreaks with similar symptoms as 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 (WHO), 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. It is well-known that patients aged older than 65 years 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 US and UK, 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 (TMPRSS2) that facilitates cell entry and subsequent viral replication.[9] ACE2 receptor is abundantly expressed in the enterocytes of the GI tract as well, mainly in the GI tract 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 causes alteration of the fecal microbiota that can damage the enterocytes, resulting in symptoms of 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] Newer studies have reported the role of the oral cavity as it serves as a portal of 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

Elevation in liver biochemistries is frequently noted 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 (ALT) predominant; however, hepatocellular injury in patients with COVID-19 infection appears to be aspartate aminotransferase (AST) predominant.[19] Due to the expression of ACE2 receptors in the cholangiocytes, mild elevation of alkaline phosphatase and gamma-glutamyl transferase (GGT) is not uncommon in patients with COVID-19.[20]

The pathogenesis of liver injury is likely multifactorial and is explained by various hypotheses that include ACE2-mediated viral replication in the liver and its resulting cytotoxicity, hypoxic or ischemic damage, immune-mediated inflammatory response, drug-induced liver injury, or 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 hepatoxic 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, the mortality rate was higher depending on their underlying Child-Pugh Class (CPC) score, with 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 the luminal GI tract cells, ACE2 is expressed in the pancreatic islet cells and pancreas microvasculature pericytes. 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 this is not specific to pancreatitis, and was not reflective of severe infection or poor clinical outcome.[25][26] However, 1 single-center prospective clinicopathologic case series study reported focal pancreatitis with necrosis of the pancreatic parenchyma and adjacent adipose tissue and calcifications in 4 patients.[27] 

Prothrombotic state

ACE2 binding to the SARS-CoV-2 virus is thought to cause endothelial damage, 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 regarding the onset and duration of symptoms, travel history, exposure to people with COVID-19, underlying medical 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 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 myalgias. However, COVID-19 can present with GI manifestations alone or concur with the other symptoms described earlier. Based on a meta-analysis studying 1992 patients, 1052 patients (53%) experienced GI symptoms, with the most commonly reported symptoms being diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%).[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 with complete blood count (CBC), a comprehensive metabolic panel (CMP) including renal and liver function testing, a coagulation panel, and serum lipase should be considered at presentation. Viral RNA 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 RNA 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 the elevation of liver biochemistries in 14% to 53% of patients.[18] AST and 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 ICU 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 GGT in patients with COVID-19.[20] Infectious etiologies, especially Clostridium difficile and other viral and bacterial enteric infections, should be ruled out in patients presenting with isolated symptoms of acute diarrhea and abdominal pain.[34]

A troponin level and an electrocardiogram (EKG) 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 (CRP), calprotectin, D-dimer, and ferritin measurement 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 illness 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 if clinically indicated with appropriate personal protective equipment (PPE) as recommended by The American Society of Gastrointestinal Endoscopy (ASGE), considering that endoscopy procedures are associated with a high risk of virus transmission.

Treatment / Management

Management of 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 (NIH) guidelines. As with other viral enteric infections, GI symptoms such as nausea and vomiting should be conservative with IV fluids, antiemetic medications, and close monitoring of serum electrolytes.

Remdesivir is the first FDA-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 when initiating the patient on remdesivir and during the course of 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 the SARS-CoV-2, and ritonavir inhibits cytochrome P450(CYP)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, with which they risk developing prothrombotic complications such as arterial and venous thrombosis. Clinicians should maintain a high index for these complications and consider initiating appropriate systemic anticoagulation, provided there are no other contraindications to starting the same.

Given that SARS-CoV-2 is an airborne pathogen, the nature of endoscopy being an aerosol-generating procedure, and the potential for possible fecal-oral transmission of SARS-CoV-2, gastroenterologists, medical staff, and endoscopy staff are at increased risk of contracting this virus or transmitting it. Following certain precautions, as described below, can prevent or reduce the transmission of the virus.[37]

 Precautions Against COVID-19 in the Endoscopy Suite

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

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 other forms of 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, CMV, EBV, or HSV 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 underlying comorbid conditions, and response to treatment. Based on a large cohort study from China involving 44,415 patients, a vast majority (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 (ICU) 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] One study found bowel wall abnormalities in 31% of abdominal CT scans (in mostly ICU patients), 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.[32][27]