The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first reported in China, in December, 2019, has posed a critical threat to global public health.1,2 The World Health Organization (WHO) has recently declared the outbreak of COVID-19 infection an international public health emergency. Lung is considered to be the primary organ of involvement by COVID-19 infection, and most patients with COVID-19 present with typical respiratory symptoms and signs. However, gastrointestinal symptoms and liver injury have also been reported to occur during the course of the disease. In this review, we assess how the digestive system and the liver are affected by COVID-19 using the available evidences to date.
2. GASTROINTESTINAL MANIFESTATIONS OF COVID-19
As SARS-CoV-2 RNA was first detected in stool of the first reported COVID-19 case in the USA, who also presented with the digestive symptoms of nausea, vomiting, and diarrhea,3 more attentions have been paid to the gastrointestinal manifestations of SARSCoV-2. Digestive symptoms including anorexia, nausea, vomiting, and diarrhea are frequently reported in patients with COVID-19 (Table 1).4–13 In the currently largest cohort including 1099 patients with laboratory-confirmed COVID-19 from 552 hospitals in 30 provinces in China through January 29, 2020, nausea or vomiting and diarrhea were reported in 55 (5%) and 42 (3.8%) patients, respectively.13
In the SARS outbreak of 2002-2003, 16% to 73% of patients with SARS had diarrhea during the course of the disease, usually within the first week of illness.14 In patients with COVID-19, diarrhea is also a common digestive symptom, with the incidence ranging from 1.3% to 29.3% (Table 1). In addition, SARS-CoV-2–induced diarrhea could be the onset symptom in patient with COVID-19.15 Nevertheless, the incidence of diarrhea varied widely among different reports, suggesting that the criteria for diagnosing diarrhea may differ in different hospitals. Clinicians might underestimate the value of digestive symptom in clinical practice, and it may affect the preliminary diagnostic accuracy.16
Pan et al17 described the clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China. Among the 204 patients with COVID-19 and full laboratory, imaging, and historical data, 99 (48.5%) presented with digestive symptoms as their chief complaint. Patients with digestive symptoms had a variety of manifestations, including anorexia (83.8%), vomiting (0.8%), diarrhea (29.3%), and abdominal pain (0.4%). Compared with patients without digestive symptoms, those presenting with digestive symptoms have a longer time from onset to admission and a worse prognosis. Notably, in 7 (3.4%) cases, there were digestive symptoms but no respiratory symptoms. Based on these findings, clinicians must be aware that digestive symptoms, such as diarrhea, may be a presenting feature of COVID-19 that arise before respiratory symptoms, and on rare occasions may be the only presenting symptom of COVID-19.
Several reports showed that the SARS-CoV-2 RNA could be detected in the stool of patients with COVID-19, implying that SARS-CoV-2 may be transmitted by the fecal–oral route.3,18,19 COVID-19 disease in a patient with positive fecal but negative pharyngeal and sputum viral tests has been reported.20 Wang et al19 showed that 44 of 153 (29%) patients with COVID-19 were tested positive for the virus in stool. Xiao et al showed that among the 73 hospitalized COVID-19 patients in China, 39 (53.42%) were tested positive for SARS-CoV-2 RNA in stool.21 The duration of positive stool ranged from 1 to 12 days, and 17 (23.29%) patients remained positive in stool after showing negative in respiratory samples. They performed endoscopic sampling of different parts of the gastrointestinal tract from a patient, and the viral RNA could be detected in esophagus, stomach, duodenum, and rectum. This study provide the direct evidence that gastrointestinal infection of SARS-CoV-2, and the infectious virions may be secreted from the virus-infected gastrointestinal cells.21
The mechanism for gastrointestinal tract infection of SARS-CoV is proposed to be the angiotensin-converting enzyme 2 (ACE2) cell receptor.22,23 SARS-CoV-2, which has the genome sequence of 82% similar to SARS-CoV, may use the same cell entry receptor ACE2, but more efficiently than the 2003 strain of SARSr-CoV.24 By analyzing endoscopic biopsy samples, Xiao et al21 showed that ACE2 was rarely expressed in esophageal epithelium, but abundantly distributed in cilia of glandular epithelia, while staining of viral nucleocapsid protein was visualized in the cytoplasm of gastric, duodenal, and rectum glandular epithelial cell, but not in esophageal epithelium. Another study also displayed that ACE2 was highly expressed in the small intestine, especially in proximal and distal enterocytes.16 The mutual interaction between SARS-CoV-2 and ACE2 might disrupt the function of ACE2 and results in diarrhea.
The possibility of fecal–oral transmission of SARS-CoV-2 emphasized the importance of frequent and proper hand hygiene, especially in areas with poor sanitation. Strict precautions must be observed when handling the stools of patients with COVID-19, and sewage from hospitals should also be properly disinfected. The presence of SARS-CoV-2 in the gastrointestinal tract also raises the concerns of COVID-19 infection in patients with preexisting digestive diseases as well as potential fecal microbiota transplant donors. Nevertheless, the comorbidity spectrum of digestive conditions and its impact on treatment and outcome of COVID-19 remains largely unknown.25 To prevent SARS-CoV-2 transmission by fecal microbiota transplantation, additional screening methodologies to the current donor screening measures should be performed.26
Finally, the gastrointestinal endoscopy departments face significant risk for transmissions of SARS-CoV-2 during endoscopy.27 In one of the earliest report of COVID-19 in Wuhan, 29% of patients (40 out of 138) were healthcare workers and suggest that the risk of infection to healthcare providers is significant.8 Possible routes of SARS-CoV-2 transmission during endoscopy examination include person-to-person, respiratory droplets, aerosols generated during endoscopy, and contact with contaminated surroundings, body fluids, and fecal material. The World Endoscopy Organization,28 the American Society for Gastrointestinal Endoscopy,29 and the European Society of Gastrointestinal Endoscopy30 have provided recommendations on the performance of endoscopy during the COVID-19 pandemic.
3. LIVER INJURY IN COVID-19
Liver injury was common in the patients infected by the other two highly pathogenic coronavirus—SARS-CoV and the Middle East respiratory syndrome coronavirus—and associated with the severity of diseases.31 In patients with COVID-19, several studies have reported the incidence of liver injury (Table 1), indicating that 2% to 11% of patients with COVID-19 had liver comorbidities and 16% to 53% cases reported abnormal levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST).32 Guan et al13 showed that elevated AST levels were observed in 18.2% of patients with nonsevere disease and 39.4% of patients with severe disease, whereas elevated ALT levels were observed in 19.8% of patients with nonsevere disease and 28.1% of patients with severe disease. Huang et al4 showed that elevation of AST was observed in 8 (62%) of 13 patients in the intensive care unit (ICU) compared with 7 (25%) of 28 patients who did not require care in the ICU. Wang et al8 also showed that patients admitted to ICU had significantly higher ALT (35 vs 23, p = 0.007) and AST (52 vs 29, p < 0.001) levels. These data suggest that liver injury is more prevalent in severe cases than in mild cases of COVID-19.
Liver injury in patients with COVID-19 might be due to viral infection in liver cells or due to other causes such as drug-induced liver injury and systemic inflammation induced by cytokine storm or pneumonia-associated hypoxia.32 SARS virus has been shown to be present in the liver tissue, although the viral titer was relatively low because viral inclusions were not observed.33 Nevertheless, a case report of pathological analysis of a patient who died from COVID-19 did not identify viral inclusions in the liver tissue.34
The impact of COVID-19 in patients with preexisting chronic liver diseases, such as viral hepatitis, nonalcoholic fatty liver disease, and alcohol-related liver disease, remains to be evaluated. The study from China showed that patients with underlying chronic hepatitis B infection did not have higher disease severity compared with the overall population.13 Currently there is no report of liver failure in COVID-19 patients with chronic liver diseases, such as chronic hepatitis B or C.
In conclusion, in this review, we summarized the recent reports of digestive symptoms and liver injury caused by COVID-19. Digestive symptoms are not uncommon in patients with COVID-19, and in some cases digestive symptoms may occur in the absence of any respiratory symptoms. COVID-19 patients with digestive symptoms have worse clinical outcomes and higher risk of mortality compared with those without digestive symptoms. Attention should also be paid to monitor liver function during the course of COVID-19, especially in patients with higher disease severity.
1. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, et al. A novel coronavirus from patients with pneumonia in China, 2019. N Engl J Med 2020;382:727–33.
2. Wu YC, Chen CS, Chan YJ. The outbreak of COVID-19: an overview. J Chin Med Assoc 2020;83:217–20.
3. Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, Spitters C, et al. First case of 2019 novel coronavirus in the United States. N Engl J Med 2020;382:929–36.
4. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497–506.
5. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020;395:507–13.
6. Xu XW, Wu XX, Jiang XG, Xu KJ, Ying LJ, Ma CL, et al. Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-CoV-2) outside of Wuhan, China: retrospective case series. BMJ 2020;368:m606.
7. Wu J, Liu J, Zhao X, Liu C, Wang W, Wang D, et al. Clinical characteristics of imported cases of COVID-19 in Jiangsu Province: a multicenter descriptive study. Clin Infect Dis 2020. In press.
8. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020. In press.
9. Shi H, Han X, Jiang N, Cao Y, Alwalid O, Gu J, et al. Radiological findings from 81 patients with COVID-19 pneumonia in Wuhan, China: a descriptive study. Lancet Infect Dis 2020;20:425–34.
10. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med 2020. In press.
11. Mo P, Xing Y, Xiao Y, Deng L, Zhao Q, Wang H, et al. Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin Infect Dis 2020. In press.
12. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020;395:1054–62.
13. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020.
14. WHO. WHO issues consensus document on the epidemiology of SARS. Wkly Epidemiol Rec 2003;78:373–5.
15. Song Y, Liu P, Shi XL, Chu YL, Zhang J, Xia J, et al. SARS-CoV-2 induced diarrhoea as onset symptom in patient with COVID-19. Gut 2020. In press.
16. Liang W, Feng Z, Rao S, Xiao C, Xue X, Lin Z, et al. Diarrhoea may be underestimated: a missing link in 2019 novel coronavirus. Gut 2020. In press.
17. Pan L, Mu M, Ren HG, Yang PC, Sun Y, Wang RS, et al. Clinical characteristics of COVID-19 patients with digestive symptoms in Hubei, China: a descriptive, cross-sectional, multicenter study. Am J Gastroenterol 2020. In press.
18. Yeo C, Kaushal S, Yeo D. Enteric involvement of coronaviruses: is faecal-oral transmission of SARS-CoV-2 possible? Lancet Gastroenterol Hepatol 2020;5:335–7.
19. Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020. In press.
20. Chen L, Luo JH, Bai Y, Wang M. COVID-19 disease with positive fecal and negative pharyngeal and sputum viral tests. Am J Gastroenterol 2020. In press.
21. Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020. In press.
22. Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science 2020;367:1444–8.
23. Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020. In press.
24. Wan Y, Shang J, Graham R, Baric RS, Li F. Receptor recognition by the novel coronavirus from Wuhan: an analysis based on decade-long structural studies of SARS coronavirus. J Virol 2020; 947e00127–20.
25. Mao R, Liang J, Shen J, Ghosh S, Zhu LR, Yang H, et al. Implications of COVID-19 for patients with pre-existing digestive diseases. Lancet Gastroenterol Hepatol 2020;5:426–8.
26. Ianiro G, Mullish BH, Kelly CR, Sokol H, Kassam Z, Ng S, et al. Screening of faecal microbiota transplant donors during the COVID-19 outbreak: suggestions for urgent updates from an international expert panel. Lancet Gastroenterol Hepatol 2020;5:430–2.
27. Repici A, Maselli R, Colombo M, Gabbiadini R, Spadaccini M, Anderloni A, et al. Coronavirus (COVID-19) outbreak: what the department of endoscopy should know. Gastrointest Endosc 2020. In press.
29. Soetikno R, Teoh AYB, Kaltenbach T, Lau JY, Asokkumar R, Cabral-Prodigalidad P, et al. Considerations in performing endoscopy during the COVID-19 pandemic. Gastrointest Endosc 2020. In press.
30. ESGE. ESGE and ESGENA Position Statement on gastrointestinal endoscopy and the COVID-19 pandemic. Update 1 (18.03.2020). Available at https://www.esge.com/esge-and-esgena-position-statement-on-gastrointestinalendoscopy-and-the-covid-19-pandemic/
31. Xu L, Liu J, Lu M, Yang D, Zheng X. Liver injury during highly pathogenic human coronavirus infections. Liver Int 2020. In press.
32. Zhang C, Shi L, Wang FS. Liver injury in COVID-19: management and challenges. Lancet Gastroenterol Hepatol 2020;5:428–30.
33. Chau TN, Lee KC, Yao H, Tsang TY, Chow TC, Yeung YC, et al. SARS-associated viral hepatitis caused by a novel coronavirus: report of three cases. Hepatology 2004;39:302–10.
34. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:420–2.