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Review article

The COVID-19 infection from the perspective of the gastroenterologist

Marija Branković1,2, Igor Jovanović1, Tijana Radonjić1, Olivera Marković1,2, Milica Brajković1, Višeslav Popadić1, Slobodan Klašnja1, Marija Zdravković1,2
  • University Hospital Medical Center Bežanijska Kosa, Belgrade, Serbia
  • Faculty of Medicine, University of Belgrade, Belgrade, Serbia

ABSTRACT

The gastrointestinal tract and liver are not spared, when it comes to the coronavirus disease of 2019 (COVID-19), as it doesn’t only affect the respiratory tract, but it is also a systemic disease that causes multiple organ damage. In this review, we have united all information that is clinically significant for physicians dealing with this infection, especially for gastroenterologists. One must bear in mind that gastrointestinal symptoms can be the first and/or only indicators of COVID-19, so this infection needs to be suspected when a patient at risk presents with diarrhea, loss of appetite, abdominal pain, nausea, and/or vomiting. Upper gastrointestinal endoscopy in the COVID-19 pandemic is a major issue, as transmission of this airborne infection happens very easily during this procedure, and it should be performed only in cases of gastrointestinal emergencies. With regard to patients suffering from inflammatory bowel disease (IBD), they are often on immunosuppressive therapy, but recommendations are that no change in therapy should be made, as these patients do not fall under the category of patients who are at increased risk of contracting COVID-19. In addition, liver lesion caused by this infection develops as the result of a multifactorial mechanism and is a definite cause for concern, especially in patients with pre-existing chronic liver conditions, who should be closely monitored.


INTRODUCTION

The first case of the coronavirus disease of 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was registered in the Chinese city of Wuhan, in December 2019 [1]. It all started when several cases of pneumonia of unknown etiology appeared in that city [2]. Now we know that severe acute respiratory syndrome coronavirus 2 is a new type of human-infecting Betacoronavirus [3]. Coronaviruses are a family of single-stranded enveloped ribonucleic acid (RNA) viruses. The genome sequence of SARS-CoV-2 is 82.0% similar to SARS-CoV [4]. SARS-CoV-2 spread quickly via respiratory droplets which resulted in a global pandemic that was, in fact, declared by the World Health Organization on March 11, 2020 [5].

Usually, the first manifestation of this disease are respiratory tract symptoms, but it is known that COVID-19 is a systemic disease with multiple organ damage. This can be explained by the receptor of angiotensin-converting enzyme 2 (ACE2) which is a way for a virus to enter a cell [6]. In alveolar cells type 2 in lungs, in the glandular cells of stomach, in epithelial cells of enterocytes in ileum and colon, in most of the cholangiocytes and in less than 3.0% of hepatocytes [7] ACE2 receptors can be found [8],[9].

THE GASTROINTESTINAL TRACT

The most commonly reported gastrointestinal tract (GIT) symptoms of COVID-19 are diarrhea, abdominal pain, nausea, vomiting and loss of appetite [10]. Gastrointestinal symptoms are present in 3.0% to 39.6% of COVID-19 patients and diarrhea is the symptom most commonly reported [6]. As already stated, COVID-19 typically affects the respiratory tract and causes fever, cough and fatigue [10], but also gastrointestinal symptoms, which can be the first and only symptoms of this infection [6].

The question of whether the gastrointestinal tract can be a potential route of transmission of this infection (fecal-oral route) remains open. Even now, after more than a year has passed since the start of the pandemic, stool samples are normally not used for diagnosing COVID-19. The nasopharyngeal swab remains the golden standard, although it has been proven that SARS-CoV-2 RNA is also present in the patients’ stool [11]. Furthermore, there is a report indicating that stool samples remained positive for SARS-CoV-2 RNA longer than nasopharyngeal swabs [12]. Therefore, it can be presumed that this mode of transmission may occur even after the virus is cleared from the respiratory tract [13].

Endoscopic procedures

Upper and lower gastrointestinal (GI) endoscopy is an issue during the COVID-19 pandemic. As such procedures require close contact of the endoscopist and the patient, there is a high risk of infection transmission, especially in case of airborne infection, like this one, with a possible fecal-oral route of transmission. This is why endoscopic procedures should be done only in case of acute gastrointestinal bleeding, and even then, sometimes, patients can be treated conservatively for upper GI bleeding with maximal doses of proton-pump inhibitors.

Upper gastrointestinal endoscopy performed in COVID-19 patients has revealed mucosal herpetic-like erosions and ulcers, and biopsy has confirmed the presence of SARS-CoV-2 [14]. As already mentioned above, upper gastrointestinal endoscopy is usually required in case of acute gastrointestinal bleeding, which is explained as a possible adverse event of low molecular weight heparin treatment, administered as prophylaxis for preventing thromboembolic events in COVID-19 infection and/or intravascular coagulation, which is often a consequence of sepsis [15].

As already mentioned, SARS-CoV-2 RNA is present in the patients’ stool [11], which is why lower endoscopy procedures also carry a high risk of infection transmission. Diarrhea and lower gastrointestinal bleeding are also frequently reported in COVID-19 patients. Lower endoscopic procedures often reveal ulcerative colonic lesions, but diverticulosis or colonic ischemia, as well (Figure 1) [15]. Ischemic colitis is thought to be the effect of hypercoagulability and endothelial dysfunction caused by SARS-CoV-2 [15].

09f01

Figure 1. Lower endoscopy findings in COVID-19 patients; Colon ischemia (A) and segmental colitis associated with diverticulosis (B)
From: https://doi.org/10.1016/j.cgh.2020.05.045. (Massironi S, Viganò C, Dioscoridi L, Filippi E, Pagliarulo M, Manfredi G, et al. Endoscopic Findings in Patients Infected with 2019 Novel Coronavirus in Lombardy, Italy. Clin Gastroenterol Hepatol. 2020;18(10):2375–2377).

Inflammatory bowel disease patients

A higher mortality rate in COVID-19 is related to advanced age, the male gender and comorbidities of the patient (arterial hypertension, diabetes mellitus, malignancies, cardiovascular and cerebrovascular diseases) [16]. In gastroenterology, there is a large number of patients with inflammatory bowel disease (IBD) and other comorbidities, who, independent of gender, belong to different age groups. Therefore, they are obviously a priority to not get infected with SARS-CoV-2. Additionally, many IBD patients are on immunosuppressive therapy or on biological therapy. Due to their treatment mechanism, these drugs lead to increased risk of infection. Since COVID-19 causes the cytokine storm, immunosuppressive drugs may prevent COVID-19 pneumonia [17]. Overall, recommendations for IBD patients suggest that they should continue with their usual therapy, since there is no evidence of increased risk of contracting the COVID-19 infection, however, these patients should be monitored closely [17].

HEPATOLOGY

After the lungs, the second organ most commonly affected by COVID-19 is the liver and there is an increase of liver enzymes in 15.0% to 53.0% of COVID-19 patients [18]. The mechanism of liver injury in COVID-19 patients is multifactorial (Figure 2).

09f02

Figure 2. Mechanisms of liver injury in COVID-19 patients

The first mechanism, which comes to mind as the most obvious one, is that the virus itself directly infects the liver and causes the development of lesions [19]. As previously mentioned, the virus enters the cell by latching onto the ACE2 receptor, which is present in most cholangiocytes and in less than 3.0% of hepatocytes [7], even though there are more patients with increased transaminases [20]. Therefore, it can be assumed that liver lesions may be caused by the infection of cholangiocytes, as ACE2 receptors are, in fact, found in cholangiocytes [7], and they participate in liver regeneration [21].

There is also the hypothesis that SARS-CoV-2 or inflammatory mediators from the intestine can use the portal circulation to invade the liver [22], as ACE2 receptors are also found in epithelial cells of enterocytes in the ileum and colon [8],[9].

Moreover, hepatotoxic drugs, especially antivirals and biological therapy targeting interleukin-6 (IL-6), but also antipyretics and antibiotics, have direct impact on liver injury in this infection [23],[24].

COVID-19-associated myositis is often seen in clinical practice, and it is known that aspartate aminotransferase (AST) is present in both liver and muscle tissue, so this may be an additional mechanism causing an increased level of AST in COVID-19 patients [24].

Furthermore, Kupffer cells, also known as hepatic macrophages, activate an inflammatory response when they encounter the SARS-CoV-2 virus [22]. Therefore, a possible mechanism of liver injury in this infection can be a systemic inflammation caused by a cytokine storm [23],[25].

Last, but not least, hypoxia happens frequently in COVID-19, due to respiratory failure. Consequently, increased transaminase levels may also be connected to ischemia in an already hypoxic liver [26].

Particular attention should, therefore, be given to COVID-19 patients with pre-existing chronic liver diseases such as cirrhosis, hepatocellular carcinoma, nonalcoholic fatty liver disease, autoimmune hepatitis and viral hepatitis, as these patients have a higher risk of decompensation and mortality [27]. In case of pre-existing chronic liver disease, it is up to the attending physician to choose the appropriate medication that can both prevent consequences of the COVID-19 infection and protect liver function.

Liver biopsy in COVID-19 patients

Pathohistological findings of liver biopsies in COVID-19 patients are necessary in order to verify or disprove the previously described mechanisms of liver injury. Within a previous study, liver biopsy was performed and the pathohistological finding showed apoptotic hepatocytes without viral inclusions, but with mild to moderate focal lobular inflammation [28]. Kupffer cell activation was indicated by immunohistochemistry [28]. Furthermore, transmission electron microscope examination revealed coronavirus particles in the cytoplasm of the hepatocytes [28]. In addition, the hepatocytes had swollen mitochondria, a dilatated endoplasmic reticulum and an impaired cell membrane, indicating that COVID-19 had caused cytopathy [28]. From the two liver biopsy cases included in this study, it can be concluded that SARS-CoV-2 can, indeed, disseminate in the liver, but there was no evidence of hypoxic-ischemic liver injury, nor of drug-induced liver injury [28].

CONCLUSION

Gastrointestinal tract symptoms and liver injury are frequently seen in KOVID-19 patients confirming it to be a systemic disease with multiple organ damage. What needs to be highlighted, as important in clinical practice, is that endoscopic procedures should be done only in case of acute gastrointestinal bleeding, in order to reduce the risk of SARS-CoV-2 transmission. Also, clinically, as IBD patients do not belong to the category of patients who are at increased risk of contracting the COVID-19 infection, the regular therapy for their chronic issues should be continued. Last, but not least, liver injury caused by COVID-19 is a real issue and these patients should be closely monitored, especially if they also have a preexisting chronic liver disease.

  • Conflict of interest:
    None declared.

Informations

Volume 2 No 4

December 2021

Pages 392-398
  • Keywords:
    COVID-19, gastrointestinal tract, liver, inflammatory bowel disease, endoscopy
  • Received:
    15 November 2021
  • Revised:
    25 November 2021
  • Accepted:
    06 December 2021
  • Online first:
    13 December 2021
  • DOI:
  • Cite this article:
    Branković M, Jovanović I, Radonjić T, Marković O, Brajković M, Popadić V, et al. The COVID-19 infection from the perspective of the gastroenterologist. Serbian Journal of the Medical Chamber. 2021;2(4):392-8. doi: 10.5937/smclk2-34920
Corresponding author

Marija Branković
University Hospital Medical Center Bežanijska Kosa
Dr Žorža Matea Street, 11000 Belgrade, Serbia
E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it.


  • 1. Villapol S. Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome. Transl Res. 2020 Dec;226:57-69. doi: 10.1016/j. trsl.2020.08.004.[CROSSREF]

    2. Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle. J Med Virol. 2020 Apr;92(4):401- 2. doi: 10.1002/jmv.25678.[CROSSREF]

    3. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020 Feb 22;395(10224):565-74. doi: 10.1016/ S0140-6736(20)30251-8.[CROSSREF]

    4. Yeo C, Kaushal S, Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol. 2020 Apr;5(4):335-7. doi: 10.1016/S2468-1253(20)30048-0.[CROSSREF]

    5. Galanopoulos M, Gkeros F, Doukatas A, Karianakis G, Pontas C, Tsoukalas N, et al. COVID-19 pandemic: Pathophysiology and manifestations from the gastrointestinal tract. World J Gastroenterol. 2020 Aug 21;26(31):4579-88. doi: 10.3748/wjg.v26.i31.4579.[CROSSREF]

    6. Schmulson M, Dávalos MF, Berumen J. Beware: Gastrointestinal symptoms can be a manifestation of COVID-19. Rev Gastroenterol Mex (Engl Ed). 2020 Jul-Sep;85(3):282-7. English, Spanish. doi: 10.1016/j.rgmx.2020.04.001.[CROSSREF]

    7. Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv. 2020;[HTTP]

    8. Zhang H, Kang Z, Gong H, Xu D, Wang J, Li Z, et al. Digestive system is a potential route of COVID-19: an analysis of single- cell coexpression pattern of key proteins in viral entry process. Gut. 2020;69:1010–8.[HTTP]

    9. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020 May;158(6):1831-33.e3. doi: 10.1053/j.gastro.2020.02.055.[CROSSREF]

    10. Baj J, Karakuła-Juchnowicz H, Teresiński G, Buszewicz G, Ciesielka M, Sitarz E, et al. COVID-19: Specific and Non-Specific Clinical Manifestations and Symptoms: The Current State of Knowledge. J Clin Med. 2020 Jun 5;9(6):1753. doi: 10.3390/jcm9061753.[CROSSREF]

    11. Hajifathalian K, Mahadev S, Schwartz RE, Shah S, Sampath K, Schnoll-Sussman F, et al. SARS-COV-2 infection (coronavirus disease 2019) for the gastrointestinal consultant. World J Gastroenterol. 2020 Apr 14;26(14):1546- 53. doi: 10.3748/wjg.v26.i14.1546.[CROSSREF]

    12. Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020 May;5(5):434-5. doi: 10.1016/S2468-1253(20)30083-2.[CROSSREF]

    13. Neurath MF. COVID-19 and immunomodulation in IBD. Gut. 2020 Jul;69(7):1335-42. doi: 10.1136/gutjnl-2020-321269.[CROSSREF]

    14. Hunt RH, East JE, Lanas A, Malfertheiner P, Satsangi J, Scarpignato C, et al. COVID-19 and Gastrointestinal Disease: Implications for the Gastroenterologist. Dig Dis. 2021;39(2):119-39. doi: 10.1159/000512152.[CROSSREF]

    15. Massironi S, Viganò C, Dioscoridi L, Filippi E, Pagliarulo M, Manfredi G, et al. Endoscopic Findings in Patients Infected With 2019 Novel Coronavirus in Lombardy, Italy. Clin Gastroenterol Hepatol. 2020 Sep;18(10):2375-7. doi: 10.1016/j.cgh.2020.05.045.[CROSSREF]

    16. Popadic V, Klasnja S, Milic N, Rajovic N, Aleksic A, Milenkovic M, et al. Predictors of Mortality in Critically Ill COVID-19 Patients Demanding High Oxygen Flow: A Thin Line between Inflammation, Cytokine Storm, and Coagulopathy. Oxid Med Cell Longev. 2021 Apr 20;2021:6648199. doi: 10.1155/2021/6648199.[CROSSREF]

    17. Monteleone G, Ardizzone S. Are Patients with Inflammatory Bowel Disease at Increased Risk for Covid-19 Infection? J Crohns Colitis. 2020 Sep 16;14(9):1334-6. doi: 10.1093/ecco-jcc/jjaa061.[CROSSREF]

    18. Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int. 2020 May;40(5):998-1004. doi: 10.1111/liv.14435.[CROSSREF]

    19. Garrido I, Liberal R, Macedo G. Review article: COVID-19 and liver disease-what we know on 1st May 2020. Aliment Pharmacol Ther. 2020 Jul;52(2):267- 75. doi: 10.1111/apt.15813.[CROSSREF]

    20. Jothimani D, Venugopal R, Abedin MF, Kaliamoorthy I, Rela M. COVID-19 and the liver. J Hepatol. 2020 Nov;73(5):1231-40. doi: 10.1016/j.jhep.2020.06.006.[CROSSREF]

    21. Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol. 2019 May;16(5):269-81. doi: 10.1038/s41575-019-0125-y.[CROSSREF]

    22. Bertolini A, van de Peppel IP, Bodewes FAJA, Moshage H, Fantin A, Farinati F, et al. Abnormal Liver Function Tests in Patients With COVID-19: Relevance and Potential Pathogenesis. Hepatology. 2020 Nov;72(5):1864-72. doi: 10.1002/hep.31480.[CROSSREF]

    23. Li J, Fan JG. Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease. J Clin Transl Hepatol. 2020 Mar 28;8(1):13-7. doi: 10.14218/ JCTH.2020.00019.[CROSSREF]

    24. Bangash MN, Patel J, Parekh D. COVID-19 and the liver: little cause for concern. Lancet Gastroenterol Hepatol. 2020 Jun;5(6):529-30. doi: 10.1016/ S2468-1253(20)30084-4.[CROSSREF]

    25. Sun J, Aghemo A, Forner A, Valenti L. COVID-19 and liver disease. Liver Int. 2020 Jun;40(6):1278-81. doi: 10.1111/liv.14470.[CROSSREF]

    26. Hajifathalian K, Krisko T, Mehta A, Kumar S, Schwartz R, Fortune B, et al.; WCM-GI research group∗. Gastrointestinal and Hepatic Manifestations of 2019 Novel Coronavirus Disease in a Large Cohort of Infected Patients From New York: Clinical Implications. Gastroenterology. 2020 Sep;159(3):1137-40. e2. doi: 10.1053/j.gastro.2020.05.010.[CROSSREF]

    27. Mohammed A, Paranji N, Chen PH, Niu B. COVID-19 in Chronic Liver Disease and Liver Transplantation: A Clinical Review. J Clin Gastroenterol. 2021 Mar 1;55(3):187-94. doi: 10.1097/MCG.0000000000001481.[CROSSREF]

    28. Wang Y, Liu S, Liu H, Li W, Lin F, Jiang L, et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol. 2020;73(4):807–16.[CROSSREF]


REFERENCES

1. Villapol S. Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome. Transl Res. 2020 Dec;226:57-69. doi: 10.1016/j. trsl.2020.08.004.[CROSSREF]

2. Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle. J Med Virol. 2020 Apr;92(4):401- 2. doi: 10.1002/jmv.25678.[CROSSREF]

3. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020 Feb 22;395(10224):565-74. doi: 10.1016/ S0140-6736(20)30251-8.[CROSSREF]

4. Yeo C, Kaushal S, Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol. 2020 Apr;5(4):335-7. doi: 10.1016/S2468-1253(20)30048-0.[CROSSREF]

5. Galanopoulos M, Gkeros F, Doukatas A, Karianakis G, Pontas C, Tsoukalas N, et al. COVID-19 pandemic: Pathophysiology and manifestations from the gastrointestinal tract. World J Gastroenterol. 2020 Aug 21;26(31):4579-88. doi: 10.3748/wjg.v26.i31.4579.[CROSSREF]

6. Schmulson M, Dávalos MF, Berumen J. Beware: Gastrointestinal symptoms can be a manifestation of COVID-19. Rev Gastroenterol Mex (Engl Ed). 2020 Jul-Sep;85(3):282-7. English, Spanish. doi: 10.1016/j.rgmx.2020.04.001.[CROSSREF]

7. Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv. 2020;[HTTP]

8. Zhang H, Kang Z, Gong H, Xu D, Wang J, Li Z, et al. Digestive system is a potential route of COVID-19: an analysis of single- cell coexpression pattern of key proteins in viral entry process. Gut. 2020;69:1010–8.[HTTP]

9. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020 May;158(6):1831-33.e3. doi: 10.1053/j.gastro.2020.02.055.[CROSSREF]

10. Baj J, Karakuła-Juchnowicz H, Teresiński G, Buszewicz G, Ciesielka M, Sitarz E, et al. COVID-19: Specific and Non-Specific Clinical Manifestations and Symptoms: The Current State of Knowledge. J Clin Med. 2020 Jun 5;9(6):1753. doi: 10.3390/jcm9061753.[CROSSREF]

11. Hajifathalian K, Mahadev S, Schwartz RE, Shah S, Sampath K, Schnoll-Sussman F, et al. SARS-COV-2 infection (coronavirus disease 2019) for the gastrointestinal consultant. World J Gastroenterol. 2020 Apr 14;26(14):1546- 53. doi: 10.3748/wjg.v26.i14.1546.[CROSSREF]

12. Wu Y, Guo C, Tang L, Hong Z, Zhou J, Dong X, et al. Prolonged presence of SARS-CoV-2 viral RNA in faecal samples. Lancet Gastroenterol Hepatol. 2020 May;5(5):434-5. doi: 10.1016/S2468-1253(20)30083-2.[CROSSREF]

13. Neurath MF. COVID-19 and immunomodulation in IBD. Gut. 2020 Jul;69(7):1335-42. doi: 10.1136/gutjnl-2020-321269.[CROSSREF]

14. Hunt RH, East JE, Lanas A, Malfertheiner P, Satsangi J, Scarpignato C, et al. COVID-19 and Gastrointestinal Disease: Implications for the Gastroenterologist. Dig Dis. 2021;39(2):119-39. doi: 10.1159/000512152.[CROSSREF]

15. Massironi S, Viganò C, Dioscoridi L, Filippi E, Pagliarulo M, Manfredi G, et al. Endoscopic Findings in Patients Infected With 2019 Novel Coronavirus in Lombardy, Italy. Clin Gastroenterol Hepatol. 2020 Sep;18(10):2375-7. doi: 10.1016/j.cgh.2020.05.045.[CROSSREF]

16. Popadic V, Klasnja S, Milic N, Rajovic N, Aleksic A, Milenkovic M, et al. Predictors of Mortality in Critically Ill COVID-19 Patients Demanding High Oxygen Flow: A Thin Line between Inflammation, Cytokine Storm, and Coagulopathy. Oxid Med Cell Longev. 2021 Apr 20;2021:6648199. doi: 10.1155/2021/6648199.[CROSSREF]

17. Monteleone G, Ardizzone S. Are Patients with Inflammatory Bowel Disease at Increased Risk for Covid-19 Infection? J Crohns Colitis. 2020 Sep 16;14(9):1334-6. doi: 10.1093/ecco-jcc/jjaa061.[CROSSREF]

18. Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int. 2020 May;40(5):998-1004. doi: 10.1111/liv.14435.[CROSSREF]

19. Garrido I, Liberal R, Macedo G. Review article: COVID-19 and liver disease-what we know on 1st May 2020. Aliment Pharmacol Ther. 2020 Jul;52(2):267- 75. doi: 10.1111/apt.15813.[CROSSREF]

20. Jothimani D, Venugopal R, Abedin MF, Kaliamoorthy I, Rela M. COVID-19 and the liver. J Hepatol. 2020 Nov;73(5):1231-40. doi: 10.1016/j.jhep.2020.06.006.[CROSSREF]

21. Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ. Cholangiocyte pathobiology. Nat Rev Gastroenterol Hepatol. 2019 May;16(5):269-81. doi: 10.1038/s41575-019-0125-y.[CROSSREF]

22. Bertolini A, van de Peppel IP, Bodewes FAJA, Moshage H, Fantin A, Farinati F, et al. Abnormal Liver Function Tests in Patients With COVID-19: Relevance and Potential Pathogenesis. Hepatology. 2020 Nov;72(5):1864-72. doi: 10.1002/hep.31480.[CROSSREF]

23. Li J, Fan JG. Characteristics and Mechanism of Liver Injury in 2019 Coronavirus Disease. J Clin Transl Hepatol. 2020 Mar 28;8(1):13-7. doi: 10.14218/ JCTH.2020.00019.[CROSSREF]

24. Bangash MN, Patel J, Parekh D. COVID-19 and the liver: little cause for concern. Lancet Gastroenterol Hepatol. 2020 Jun;5(6):529-30. doi: 10.1016/ S2468-1253(20)30084-4.[CROSSREF]

25. Sun J, Aghemo A, Forner A, Valenti L. COVID-19 and liver disease. Liver Int. 2020 Jun;40(6):1278-81. doi: 10.1111/liv.14470.[CROSSREF]

26. Hajifathalian K, Krisko T, Mehta A, Kumar S, Schwartz R, Fortune B, et al.; WCM-GI research group∗. Gastrointestinal and Hepatic Manifestations of 2019 Novel Coronavirus Disease in a Large Cohort of Infected Patients From New York: Clinical Implications. Gastroenterology. 2020 Sep;159(3):1137-40. e2. doi: 10.1053/j.gastro.2020.05.010.[CROSSREF]

27. Mohammed A, Paranji N, Chen PH, Niu B. COVID-19 in Chronic Liver Disease and Liver Transplantation: A Clinical Review. J Clin Gastroenterol. 2021 Mar 1;55(3):187-94. doi: 10.1097/MCG.0000000000001481.[CROSSREF]

28. Wang Y, Liu S, Liu H, Li W, Lin F, Jiang L, et al. SARS-CoV-2 infection of the liver directly contributes to hepatic impairment in patients with COVID-19. J Hepatol. 2020;73(4):807–16.[CROSSREF]

1. Villapol S. Gastrointestinal symptoms associated with COVID-19: impact on the gut microbiome. Transl Res. 2020 Dec;226:57-69. doi: 10.1016/j. trsl.2020.08.004.[CROSSREF]

2. Lu H, Stratton CW, Tang YW. Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle. J Med Virol. 2020 Apr;92(4):401- 2. doi: 10.1002/jmv.25678.[CROSSREF]

3. Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020 Feb 22;395(10224):565-74. doi: 10.1016/ S0140-6736(20)30251-8.[CROSSREF]

4. Yeo C, Kaushal S, Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol. 2020 Apr;5(4):335-7. doi: 10.1016/S2468-1253(20)30048-0.[CROSSREF]

5. Galanopoulos M, Gkeros F, Doukatas A, Karianakis G, Pontas C, Tsoukalas N, et al. COVID-19 pandemic: Pathophysiology and manifestations from the gastrointestinal tract. World J Gastroenterol. 2020 Aug 21;26(31):4579-88. doi: 10.3748/wjg.v26.i31.4579.[CROSSREF]

6. Schmulson M, Dávalos MF, Berumen J. Beware: Gastrointestinal symptoms can be a manifestation of COVID-19. Rev Gastroenterol Mex (Engl Ed). 2020 Jul-Sep;85(3):282-7. English, Spanish. doi: 10.1016/j.rgmx.2020.04.001.[CROSSREF]

7. Chai X, Hu L, Zhang Y, et al. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019-nCoV infection. bioRxiv. 2020;[HTTP]

8. Zhang H, Kang Z, Gong H, Xu D, Wang J, Li Z, et al. Digestive system is a potential route of COVID-19: an analysis of single- cell coexpression pattern of key proteins in viral entry process. Gut. 2020;69:1010–8.[HTTP]

9. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology. 2020 May;158(6):1831-33.e3. doi: 10.1053/j.gastro.2020.02.055.[CROSSREF]

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