Brigham and Women's Hospitals

Gastroenterology

Updated: June 10, 2020

GI symptoms

Overview

  1. Incidence:
  1. <10% to 60% patients have GI symptoms on presentation incidence appears to be much higher in the US as compared to China (Sultan et al, Gastroenterology, 2020; Redd et al, Gastroenterology, 2020).
  2. The incidence of GI symptoms may be higher among those with severe pulmonary disease (Sultan et al, Gastroenterology, 2020), though such findings have not been consistent among studies thus far.
  1. GI symptoms:
  1. In general, anorexia is the most common gastrointestinal symptom followed by diarrhea and nausea. Vomiting and abdominal pain are not as common (Luo et al, Clin Gastro Hepatol, 2020; Pan et al, The Am J Gastroenterol, 2020).
  1. In an analysis of the presenting symptoms and clinical outcomes of 318 adult patients with COVID-19 who were admitted to 9 hospitals across Massachusetts, 61% reported at least one gastrointestinal symptom (35% w/anorexia, 34% w/diarrhea, 26% w/nausea, 15% w/vomiting, and 15% w/abdominal pain) (Redd et al, Gastroenterology, 2020).
  1. Diarrhea attributed to COVID-19 is often mild (mean # of bowel movements per day = 3-4, range = 2-10) and usually persists for <1 week (mean # of days = 4-5, range = 1-14). High volume or clinically severe diarrhea is not common (Han et al, Am J Gastroenterol, 2020; Jin et al, Gut, 2020; Lin et al, Gut, 2020).
  2. Abdominal pain has been described as “stomachache, epigastric pain, and abdominal discomfort;” further characteristics have not been reported (Sultan et al, Gastroenterology, 2020).
  1. Clinical course:
  1. GI symptoms may be the initial or predominant presenting symptom in 15-20% of patients (Redd et al, Gastroenterology, 2020).
  2. Most patients who present with GI symptoms already have radiographic evidence of pulmonary involvement (Luo et al, Clin Gastro Hepatol, 2020) and will eventually develop pulmonary symptoms (sometimes as quickly as 1-2 days later) (Amirian, Int J Infect Dis, 2020; Pan et al, The Am J Gastroenterol, 2020).
  3. Very few patients have only GI symptoms throughout the course of illness, though such presentations have been reported (Pan et al, The Am J Gastroenterol, 2020).
  1. Imaging and pathology:
  1. Imaging correlates in patients with GI symptoms are not well understood yet, in part because imaging is not routinely performed in those with mild GI symptoms. A fluid-filled colon appears to be a common finding on CT abdomen/pelvis. Radiographic evidence of colitis / enteritis (and rarely, bowel infarction) has been seen in critically ill patients (Bhayana et al, Radiology, 2020).
  1. Pathophysiology:
  1. Different mechanisms may mediate the broad array of GI symptoms seen in COVID-19. Proposed mechanisms include:
  1. Direct damage to the intestinal mucosa via viral infection (with positive immunofluorescent staining for the viral nucleocapsid protein being seen in biopsies from the stomach, duodenum, and rectum) (Xiao et al, Gastroenterology, 2020)
  2. Hypercoagulable state leading to bowel ischemia via a) microthrombi in the lamina propria and submucosa; or b) less commonly, large vessel thrombosis (Bhayana et al, Radiology, 2020; Ignat et al, Surgery, 2020)
  3. Indirect alterations in mucosal immunity via the “gut-lung axis” (Pan et al, The Am J Gastroenterol, 2020)
  4. Adverse medication effects or secondary infections, especially if symptoms arise later in the course of disease.
  5. Secondary effects of anosmia and ageusia (especially with respect to anorexia) (Redd et al, Gastroenterology, 2020)

Workup

  1. COVID-19 testing is not currently recommended for patients presenting with mild GI symptoms in the absence of other COVID-19 symptoms.
  1. Patients should be educated that gastrointestinal symptoms may precede the onset of respiratory symptoms and be given strict return precautions.
  1. In patients with suspected or known COVID-19 disease, remember to consider non-COVID-19 etiologies as well as secondary complications from COVID-19 (such as portal / mesenteric thrombosis) in the differential for gastrointestinal symptoms.
  1. Workup will depend on the nature and severity of the symptoms:
  1. Basic laboratories to be included on presentation are described in Diagnostics.
  2. More extensive laboratory evaluation (such as lipase, amylase, lactate, stool studies) and more extensive imaging (such as KUB, CT abdomen / pelvis, abdominal US +/- dopplers, or pelvic US) may be indicated.
  1. Do not miss critical conditions due to concerns about transport to imaging.
  2. Rule out Clostridium difficile in patients with diarrhea.
  1. Surgical and/or gastroenterology consultation may be indicated.

Management

  1. The gastrointestinal manifestations of COVID-19 (such as diarrhea, loose stool, nausea, vomiting, abdominal pain) are generally mild and transient.
  1. Treat nausea and diarrhea symptomatically, replete electrolytes, and be judicious in the use of IV fluids to replace gastrointestinal losses.
  2. If symptoms are not mild and transient, consider alternative etiologies, including drug side effects, secondary infections, bowel ischemia (see below), etc.

Bowel infarction

Overview

  1. Prevalence:
  1. Bowel infarction in COVID-19 appears to be rare, but cases reports are emerging (all in critically ill patients). In one retrospective study, abdominal imaging findings were analyzed in all patients admitted to the ICU (33%) or floor (67%) over a 2-week period. The most common indications to obtain a CT a/p were abdominal pain (33%) and sepsis (29%). Among the CT a/p scans performed in ICU patients (n = 20), the following findings were seen: fluid-filled colon in 65%, colonic or rectal thickening in 20%, small bowel wall thickening in 25%, pneumatosis or portal vein gas in 20% (n = 4), and perforation in 5% (n = 1). Among the CT a/p scans performed in non-ICU patients (n = 22), the following findings were seen: fluid-filled colon in 23% and colonic or rectal thickening in 14%; none of the non-ICU patients had findings of small bowel wall thickening, pneumatosis or portal vein gas, or perforation (Bhayana et al, Radiology, 2020).
  1. Pathophysiology
  1. Bowel infarction in COVID-19 appears to be associated with microthrombi in the submucosa, though there are also case reports of large-vessel thrombosis.
  1. There are at least 3 case reports of patients with evidence of bowel ischemia on imaging but without large-vessel thrombosis who went to laparotomy. Findings on subsequent examination of the excised bowel have included: diffuse ischemic injury with multifocal mucosal necrosis and fibrin thrombi / microthrombi in submucosal arterioles beneath the necrotic mucosa (Bhayana et al, Radiology, 2020; Ignat et al, Surgery, 2020).
  2. There are at least 2 case reports of patients with evidence of bowel infarction on imaging due to large-vessel thrombosis (PVT and SMV thrombosis). One patient had evidence of baseline hypercoagulability and prior PVT; the other patient had no known medical history (Ignat et al, Surgery, 2020; de Barry et al, Radiol Case Rep, 2020).

Liver injury

Overview

  1. Incidence:
  1. Elevated liver biochemistries (defined as AST, ALT, ALP, or bilirubin > ULN) are common and are seen in:
  1. Some patients before the onset of symptoms (Shi et al, Lancet Infect Dis, 2020)
  2. 15-70% of patients on presentation (incidence appears to be higher in the US as compared to China) (AASLD Clinical Insights, Updated May 14, 2020; Bloom et al, Hepatology, 2020)
  3. >90% of patients during the course of illness (Bloom et al, Hepatology, 2020)
  1. Liver injury (defined as AST or ALT > 3x ULN; ALP and/or bilirubin > 2x ULN) is uncommon in presentation, but it does the course of illness, especially in those who are critically ill (Bloom et al, Hepatology, 2020).
  2. Both the incidence and degree of elevation in liver biochemistries are higher in severe disease (as compared to non-severe-disease).
  1. AST is significantly higher on admission and during the course of admission in patients with severe disease (Lei et al, Hepatology, 2020).
  2. Liver injury is associated with increased length of admission, need for ICU admission, and mortality (Fan et al, Clin Gastroenterol Hepatol, 2020; Lei et al, Hepatology, 2020; Hajifathalian et al, World J Gastroenterol, 2020).
  1. Pattern of liver biochemistries:
  1. On presentation, abnormalities are predominantly hepatocellular and mild (even in severe disease). (Lei et al, Hepatology, 2020; AASLD Clinical Insights, Updated May 14, 2020):
  1. AST > ALT.
  2. AST and ALT elevations are usually 1-2x ULN on presentation. Levels are higher in patients with severe disease.
  3. GGT is often elevated, but ALP is normal.
  4. Low levels of albumin are very common, but abnormalities in other markers of synthetic function, namely bilirubin and prothrombin time, are rare.
  1. Less is known about the trajectory of abnormalities during the course of illness, in part due to variations in clinical course and drug exposures. (Lei et al, Hepatology, 2020; Bloom et al, Hepatology, 2020):
  1. AST and ALT:
  1. May rise to >3x ULN in 40% of patients. Peak levels are significantly higher in patients with severe disease. In one study, median peak AST and ALT was <3x ULN in non-intubated patients but >3x ULN in intubated patients (Bloom et al, Hepatology, 2020).
  1. ALP:
  1. ALP > 2x ULN is seen in <5% of patients during the course of illness
  1. T bili:
  1. T-bili > 2x ULN is seen in <10% of patients during the course of illness)
  1. In critically ill patients, late cholestasis (w/preserved synthetic function) is more common (Cardoso et al, Crit Care, 2020)
  1. Acute liver failure has not been reported, even in those who are severely ill and in those with chronic liver disease (AASLD Clinical Insights, Updated May 14, 2020).
  1. Imaging and pathology:
  1. In ICU patients, the most common finding on RUQUS (for evaluation of LFT abnormalities) appears to be gallbladder sludge (59%), with or without distention. Data on RUQUS findings in non-ICU patients is limited. In one retrospective study, abdominal imaging findings were analyzed in all patients admitted to the ICU (33%) or floor (67%) over a 2-week period. The most common indication to obtain a RUQUS was elevated LFTs (86%). Among the RUQ ultrasounds performed in ICU patients (n = 32), the following findings were seen: gallbladder sludge and distention in 59%, gallbladder sludge without distention in 6% (n = 2), increased gallbladder wall thickness in 3% (n = 1), pericholecystic fluid in 3% (n = 1), and fatty liver in 25%. Among the RUQ ultrasounds performed in non-ICU patients (n = 5), the following findings were seen: gallbladder sludge and distention (n = 1) and fatty liver (n = 2) (Bhayana et al, Radiology, 2020).
  1. While no cases of portal vein thrombus were seen in the study described above (Bhayana et al, Radiology, 2020), there have been at least two case reports of PVT in critically ill patients with COVID-19 (see “GI symptoms” section above).
  1. A limited number of post-mortem liver examinations have shown relatively non-specific findings, including: moderate microvesicular steatosis; mild, mixed lobular and portal activity; mild sinusoidal dilation with mildly increased small lymphocytes infiltration in sinusoidal spaces; and multifocal hepatic necrosis (Li and Xiao, J Med Virol, 2020).
  1. Pathophysiology:
  1. Hypothesized pathways for liver injury include: a direct viral cytopathic effect (ACE2 is expressed on cholangiocytes and, to a lesser extent, hepatocytes); altered hepatic perfusion secondary to microthrombi; and cytokine-mediated injury (Zhang et al, Lancet Gastroenterol Hepatol, 2020; Bloom et al, Hepatology, 2020).
  2. In critically ill patients, liver injury may be secondary to ischemic / hypoxic hepatitis (“shock liver”); hepatic congestion (secondary to elevated right atrial pressures and impaired venous return); and cholestasis of sepsis (Bangash et al, Lancet Gastroenterol Hepatol, 2020).
  3. Hepatotoxic medications may also contribute. The hepatotoxicity of therapies under investigation in COVID-19 is described below:
  1. Remdesivir. Increases in liver enzymes were seen in 23% receiving compassionate-use remdesivir (Grein et al, NEJM, 2020). In the Gilead Phase 3 SIMPLE trial, 7% developed grade 3 or higher liver enzyme elevations with 3% discontinuing remdesivir due to elevated liver biochemistries (Gilead Press Release, 2020).
  2. Tocilizumab. 20-40% have mild elevations in ALT (1-3x ULN), but such elevations are asymptomatic, not associated with elevations in ALKP or bilirubin, and resolve in 4-8 weeks after infusion; <1% experience ALT elevation >3x ULN. Rarely, tocilizumab has been associated with clinically apparent liver injury with jaundice (usually arising after several months of therapy). Tocilizumab has not been implicated in causing reactivation of hepatitis B, but safety in chronic hepatitis B and C is not well understood (Liver Tox (NCBI), 2015).
  3. Sarilumab. 15-25% have mild elevations in ALT (1-3x ULN) (AASLD Clinical Insights, Updated May 14, 2020).
  4. Chloroquine and hydroxychloroquine. Chloroquine and hydroxychloroquine are not associated with significant elevations in serum aminotransferases. Clinically significant liver injury is very rare (except in patients with porphyria cutanea tarda) (Liver Tox (NCBI), 2018).
  1. Lastly, elevated AST levels may be partially attributable to myositis or myocarditis (independent of hepatic injury) (Li and Xiao, J Med Virol, 2020). However, elevated AST probably represents true hepatic injury in most patients (AST remains highly correlated with ALT during admission, but not with CK and LDH) (Bloom et al, Hepatology, 2020).

Workup

  1. Laboratory testing (also see Diagnostics):
  1. On admission, obtain full liver panel (including AST, ALT, ALKP, total bilirubin, direct bilirubin, albumin, total protein, and PT-INR) as well as LDH, CK, and troponin (to assess for component of myositis / myocarditis)
  2. During admission, trend LFTs and INR:
  1. Daily if the patient is in the ICU, initial LFTs are abnormal; or the patient is being treated with hepatotoxic medications
  2. Every other day in other inpatients
  1. Hepatitis B and C serologies should also be sent prior to initiation of immune modulating therapies (such as IL-6 antagonists tocilizumab or sarilumab).
  1. Imaging:
  1. In general, hepatic imaging is not needed in patients with asymptomatic, mild, hepatocellular-predominant elevations in liver biochemistries.
  2. Imaging should be considered in patients with concerning symptoms or signs, such as RUQ pain, ascites, atypical pattern of elevation (i.e. cholestatic), liver injury (AST or ALT >3x ULN; ALP or T-bili >2x ULN), or at risk for PVT.
  1. The decision to obtain RUQUS (+/- dopplers) vs CT a/p will depend on the clinical scenario. Discuss with radiology and/or GI if guidance is needed.
  2. MRI/MRCP may be indicated in certain situations. Discuss with radiology and/or GI before ordering to avoid unnecessary imaging.
  1. For patients who present with or develop elevations in liver biochemistries, the differential and workup will depend on the severity and pattern of injury.
  1. Consider drug-induced liver injury
  1. Review exposures The “synopsis” tab in Epic is particularly helpful for reviewing medication exposures during long admissions
  1. If the patient is on an investigational or off-label therapeutic, discuss risk / benefit of continuation with ID.
  2. Statins may be beneficial in COVID-19. Mild elevations in liver biochemistries do not warrant discontinuation of statin therapy. Consider holding statin if CK > 500 U/L or ALT > 3x ULN (Bloom et al, Hepatology, 2020).
  1. Consider secondary insults related to critical illness (such as drugs, ischemia, congestion)
  2. Consider viral hepatitis
  1. AASLD recommends serologic testing for hepatitis B and C in all patients who present with (or develop) elevated liver biochemistries HBV surface antigen, HBV surface antibody, HBV core IgM antibody, HBV core total antibody, and HCV antibody
  2. Testing for hepatitis A, hepatitis E, or herpes viruses may be indicated depending upon patient risk factors and the pattern / severity of elevation
  1. Consider biliary, vascular, infiltrative, and immune-mediated etiologies
  2. Consider non-hepatic etiologies (i.e. myositis, myocarditis)

Management

  1. Liver injury is most often mild and self-resolving. No specific therapy is typically needed (AASLD Clinical Insights, Updated May 14, 2020).
  2. Consult GI / hepatology if:
  1. There is concern for significant underlying liver disease (see “Special populations in GI” below)
  2. There is concern for portal vein thrombus on US or CT
  3. The pattern of liver injury does not fit with the mild, hepatocellular elevations characteristically seen in COVID-19 (i.e. cholestatic pattern or significantly impaired synthetic function)
  4. The liver injury is severe or significantly worsening, especially if concern for acute liver failure (which is defined as severe acute liver injury with encephalopathy and an INR of ≥ 1.5)

Elevated pancreatic enzymes

Overview

  1. Incidence:
  1. Hyperlipasemia, defined as a lipase level above the upper limit of normal, has been seen in 12-18% of patients (McNabb et al, Gastroenterology, 2020; Wang et al, Gastroenterology, 2020).
  2. However, a lipase level >3 times the upper limit of normal appears to be rare (seen in only 2-3% of patients in whom lipase was checked) and no cases meeting diagnostic criteria for acute pancreatitis (as per the Revised Atlanta Classification) have been reported (McNabb et al, Gastroenterology, 2020).
  3. In one study, hyperlipasemia was more common in patients with severe disease (seen in 1-2% of patients with mild disease vs 17-18% of patients with severe disease) (Liu et al, Clin Gastroenterol and Hepatol, 2020), but in another study, hyperlipasemia was not associated with severity of disease (McNabb et al, Gastroenterology, 2020).
  1. Clinical presentation:
  1. Gastrointestinal symptoms are common in patients with hyperlipasemia (11-67% with anorexia, 56% with nausea, 11-57% with diarrhea, 33% with general abdominal discomfort) (McNabb et al, Gastroenterology, 2020, Wang et al, Gastroenterology, 2020).
  1. Pathophysiology:
  1. A direct viral cytopathic effect on the pancreas is possible, as the ACE2 is expressed in both the exocrine glands and islet cells of the pancreas (Liu et al, Clin Gastroenterol and Hepatol, 2020).
  2. Amylase and lipase elevations may not be related to pancreatic inflammation and may be secondary to gut inflammation (enteritis/colitis), renal injury, and/or diabetes. (Jin et al, Gastroenterology 2019; McNabb et al, Gastroenterology, 2020; de-Madaria et al, Gastroenterology, 2020; Hameed et al, HPB, 2015).

Workup and Management

  1. In patients with elevated lipase and abdominal pain / tenderness, CT a/p is recommended to clarify the differential, including pancreatitis vs enteritis / colitis vs bowel ischemia or obstruction vs cholecystitis or other hepatobiliary process (all of which can cause elevated lipase and abdominal pain) (Hameed et al, HPB, 2015).
  1. Such patients require surgery or gastroenterology consultation depending on their exam and imaging findings.
  1. In patients with elevated lipase but without abdominal pain or other concerning symptoms, look for alternative etiologies of elevated lipase (such as renal impairment) and monitor clinically.

Special Populations in GI

Cirrhosis and chronic liver diseases

  1. Overview
  1. Chronic liver disease (including NAFLD) is a risk factor for severe disease and increased mortality. Cirrhotics and liver transplant recipients are at particularly high risk of death (Ji et al, Journal of Hepatology, 2020; Singh and Khan, Gastroenterology, 2020; Lee et al, Gastroenterology, 2020).
  1. The SECURE-Cirrhosis and COVID-Hep registries are tracking data on patients (throughout the world) with cirrhosis, chronic liver disease, and liver transplant who are infected with COVID-19 (Weekly Update, last updated May 4, 2020). Data thus far shows:
  1. Patients w/non-cirrhotic chronic liver disease: 18% required ICU admission and 6% died.
  2. Patients s/p liver transplant: 22% required ICU admission and 22% died.
  3. Patients w/cirrhosis: 24% required ICU admission and 37% died. Unfortunately, poorer outcomes in cirrhosis are not unexpected. Among patients with ARDS of any cause, cirrhotic patients are known to have poorer outcomes (increased 90-day mortality) as compared to non-cirrhotic patients (Gacouin et al, Shock, 2016).
  1. 38% experienced a decompensating event (either ascites or encephalopathy, very rarely variceal bleeding) during the course of illness
  1. Management
  1. The American Association for the Study of Liver Diseases (AASLD) has constructed a ‘living document’ on best clinical practices in hepatology during the COVID-19 pandemic: AASLD "Clinical Best Practice Advice for Hepatology and Liver Transplant Providers during the COVID-19 Pandemic," last accessed May 14, 2020.
  2. We recommend GI / hepatology consultation for COVID-19 patients with:
  1. Decompensated cirrhosis
  2. Chronic HBV or HCV infection
  3. Autoimmune hepatitis
  4. Immune checkpoint-inhibitor (ICI) hepatitis
  5. S/p orthotopic liver transplant (OLT)
  6. Other serious liver disease
  1. For patients with compensated cirrhosis, the utility of a GI / hepatology consultation can be discussed with the consult team.

Inflammatory bowel disease

  1. Overview
  1. The SECURE-IBD registry (SECURE-IBD Registry) is a joint collaboration between Mount Sinai and the University of North Carolina that launched in March 2020 to better understand the impact of COVID-19 on IBD patients.
  1. As of May 8, 2020, there were 1170 reported cases of COVID-19 in IBD patients (379 of which were in the US).
  1. Among the 1170 cases, 32% required hospitalization, 6% required ICU admission, 5% required mechanical ventilation, and 4% died.
  2. Among the 1170 cases, 58% were in remission. Among those in remission, 28% required hospitalization; 30% and 44% of those with mild and moderate-severe disease activity required hospitalization, respectively.
  1. Cohort studies from Italy and Spain suggest that patients with IBD (including those on biologics or immunomodulators) have an overall good prognosis (Norsa et al, Gastroenterology, 2020; Rodriguez-Lago et al, Gastroenterology, 2020).
  2. Patients on prednisone (> 20 mg daily) are likely at increased risk of COVID-19. It is unclear if the risk and severity of infection are increased in patients on thiopurines (azathioprine, 6-mercaptopurine), methotrexate, anti-TNF therapies (infliximab, adalimumab, certolizumab, golimumab), vedolizumab, ustekinumab, and the JAK inhibitor tofacitinib (Rubin et al, Gastroenterology, 2020).
  1. Management
  1. Recommendations from the International Organization for the Study for Inflammatory Bowel Disease on the management of IBD during the COVID-19 pandemic are now published (Rubin et al, Gastroenterology, 2020).
  2. We recommend GI / hepatology consultation for all COVID-19 patients with IBD.

Fecal Microbiota Transplant (FMT) in Clostridium difficile infection

  1. Overview:
  1. The FDA has issued an alert recommending that stool used for FMT should have been donated prior to December 1, 2019 but does not prohibit FMT if deemed necessary (FDA Safety Alert).
  1. Management
  1. We currently recommend holding the use of FMT until further donor screening protocols as well as endoscopic safety and logistic considerations are in place for COVID-19.

Patients in need of endoscopic procedures

  1. Both upper and lower endoscopy are considered aerosolizing procedures.
  2. Triage recommendations as well as PPE recommendations in endoscopy are as follows:
  1. Guidance from the US GI societies (AGA, ACG, ASGE, AASLD) can be found here:
  1. Joint GI Society, Clinical Insights for Gastroenterologists, March 2020.
  2. Joint GI Society, Guidance on Endoscopic Procedures, March 2020.
  3. Joint GI Society Statement, Statement on the Use of PPE in Endoscopy, April 2020.
  1. Guidance from the European Society of Gastroenterology and Endoscopy Nurses and Associates can be found here:
  1. ESGE / ESGENA, Position Statement on Endoscopy, April 2020.
  1. A comparison of guidance from endoscopic societies worldwide, including Wuhan, Hong Kong, Australia, Canada, US, UK, and European societies, can be found here: Lui et al, JGH, 2020.
  1. Consult GI / hepatology for questions about decisions to proceed with or defer endoscopic procedures during the pandemic.