|Year : 2020 | Volume
| Issue : 1 | Page : 21-25
COVID-19: Gut and liver
Deepanshu Paliwal, Swati Rajput, Satyavati Rana
Department of Biochemistry, AIIMS, Rishikesh, Uttarakhand, India
|Date of Submission||23-May-2020|
|Date of Decision||07-Jun-2020|
|Date of Acceptance||17-Jun-2020|
|Date of Web Publication||20-Jul-2020|
Dr. Satyavati Rana
Department of Biochemistry, AIIMS, Rishikesh, Uttarakhand
Source of Support: None, Conflict of Interest: None
Currently, the world is facing a pandemic induced by novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), termed as coronavirus disease 2019 (COVID-19). Patients typically present with myalgia, fever and respiratory symptoms, but studies have stated the existence of gastrointestinal (GI) symptoms, liver injury and existence of SARS-CoV-2 RNA in the faecal specimen of these individuals. GI symptoms were also common during the previous outbreak of coronavirus family, i.e., severe acute respiratory syndrome and Middle East respiratory syndrome in 2003 and 2012, respectively. Literature reports multiple studies with varied proportions of GI symptoms such as abdominal pain, nausea, vomiting and diarrhoea. Hepatic injury was assessed with abnormal serum levels of aspartate aminotransferase, alanine aminotransferase and total bilirubin. SARS-CoV-2 may enter host cells by the presence of angiotensin-converting enzyme-2 receptor which is present in enterocytes (in small intestine), cholangiocytes (in bile duct) and hepatocytes (in liver) suggesting replication of virus in intestine and liver. This might be the cause of dysregulation of liver and GI functions. Another possible mechanism of dysregulation of the intestinal and hepatic systems might include inflammatory cytokine storm or antibiotic-induced toxicity. This article discusses a possible faecal-oral transmission due to viral shedding in the stool. This review article also emphasises on GI and hepatic aspects of COVID-19 which might become a defining tool in our fight against it.
Keywords: Coronavirus, coronavirus disease 2019, cytokines, enterocyte, myalgia, pandemic, severe acute respiratory syndrome coronavirus 2, viral shedding
|How to cite this article:|
Paliwal D, Rajput S, Rana S. COVID-19: Gut and liver. J Med Evid 2020;1:21-5
| Introduction|| |
Novel coronavirus is presently causing a major pandemic around the world. In accordance with WHO coronavirus disease 2019 (COVID-19), Situation Report-107 at 10:00 CEST, 6 May 2020, there are 3,588,773 confirmed cases and 247,503 deaths around the globe. The disease is termed as COVID-19, and the novel coronavirus responsible for this disease is called as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus is an enveloped, positive-sense RNA virus with spike protein on its surface. The disease is speculated to have started in Wuhan, the capital of Hubei province in China. Patients with this infection who typically present with fever, cough, myalgia, fatigue and symptoms of mild respiratory tract infection,, to severe pneumonia may progress to acute respiratory infection or multi-organ dysfunction or acute respiratory distress syndrome (ARDS). Less clarity is seen in case of the extrapulmonary complications of SARS-CoV-2; nevertheless, many reports have surfaced showing some incidence of gastrointestinal (GI) symptoms, comprising abdominal discomfort or pain, vomiting, diarrhoea and nausea. Some reports have also surfaced showing abnormal liver profile or liver injury in patients suffering from this disease.,,
Pulmonary manifestations were seen in previous outbreaks by other members of coronavirus, i.e., Middle East respiratory syndrome (MERS) in the Middle East and severe acute respiratory syndrome (SARS) in China in 2012 and 2003, respectively. SARS, MERS and SARS-CoV-2 are considered to have been arisen in bats. GI symptoms such as diarrhoea, nausea and vomiting were also prevalent during these outbreaks caused by SARS and MERS. This study tends to summarise the information, implications and possible mechanisms of SARS-CoV-2 infection with respect to GI and hepatic pathologies.
| Multiple Studies Highlighting Gastrointestinal Manifestations|| |
An early study from Wuhan in China which collected data from 140 COVID-19 patients reported 39.6% of individuals with GI symptoms which include nausea in 17.3%, diarrhoea in 12.9% and vomiting in 5% of the individuals. Two interesting studies also came from China. Jin et al. analysed 651 individuals infected from SARS-CoV-2, out of which 74 patients showed at least 1 GI symptom, i.e., vomiting, diarrhoea or nausea. They found that up to 28.38% of patients did not have any respiratory symptoms but were showing GI symptoms. They also found that the rate of severity of the disease was greater in individuals with GI symptoms in contrast to patients without any GI symptoms (22.97% vs. 8.14%). The second study by Lin et al. also focused on GI symptoms of COVID-19 by analysing 95 patients. Out of these 95, 61.1% of cases were documented to have GI symptoms which included diarrhoea in 24.2%, vomiting in 4.2% and nausea in 17.9%. They also performed endoscopy in 6 patients, and biopsies were taken. SARS-CoV-2 RNA was present in the biopsies of 2 severe cases in their stomach, oesophagus, duodenum and rectum specimens. Duodenal biopsy was found to be positive in one out of the four non-severe patients. They also analysed faecal samples of 68 individuals: 45 with GI symptoms and 23 without GI symptoms. Out of these, 22/45 (52.4%) and 9/23 (39.1%) presented SARS-CoV-2 RNA in their faecal samples, respectively. Therefore, both the studies show frequency of GI symptoms during the SARS-CoV-2 infection.
A study by Holshue et al., which mentions the first case of COVID-19 in USA, showed viral RNA on the 7th day of illness in the faecal specimen. Literature has shown the presence of SARS-CoV-2 RNA in the faecal specimen for a longer duration even if the patient is asymptomatic or the respiratory sample has been tested negative. In an investigation by Xiao et al. which analysed 73 COVID-19-hospitalised individuals in China, a total of 53.4% of individuals were positive for duration of day 1 to day 12 for the virus. The study also described that 23.29% of individuals had a negative respiratory sample but continued to be tested positive in the stool. These studies might indicate a correlation between GI tract and SARS-CoV-2 pathogenesis, but clarity of the matter is still ambiguous, and more clinical evidence is required. A study reported that stool specimens were as precise as the respiratory samples. Testing the faecal specimen over the respiratory swab sample shows a possibility that may reduce the infection towards the medical staff. The study also comprehends that the severity of the respiratory infection was not correlated with the faecal specimen. Some intriguing results also came from Singapore reporting about 50% of the patients with positive faecal results, but only half of the patients reported the GI symptoms. Furthermore, there are studies which investigate COVID-19 in paediatric patients. As in their adult counterparts, children also showed the similar GI symptoms. In a group of 171 paediatric patients, 15 (8.8%) had diarrhoea and 11 (6.4%) had vomiting. Another study which focussed on viral shedding in 10 paediatric patients found that 8 of them tested positive for rectal swabs even after negative nasopharyngeal swab results. These studies might also suggest a faecal-oral transmission of the virus mainly due to its shedding in the stool of the patients [Table 1].
From the data present in [Table 1], it is evident that SARS-CoV-2 might be causing GI symptoms such as vomiting (1%–6.4%), diarrhoea (2%–38.8%) and nausea (1%–17.3%). Diarrhoea might be one of the initial symptoms and may even occur before the respiratory symptoms and pyrexia in some cases. Patients with co-morbidities associated with the infection of COVID-19 have generally poorer results. Cancer patients are considered to have increased susceptibility to the disease. It would be interesting to note whether individuals suffering from cancers of GI regions are considered to be more vulnerable to the infection from SARS-CoV-2 compared to a healthy individual. Individuals suffering from cancer and SARS-CoV-2 infection have greater chances to embark on severe events during the infection. Management of individuals with pre-existing GI conditions is also crucial. Literature reported that in case of patients suffering from inflammatory bowel disease, a death was seen in a case of a senior individual suffering from severe acute ulcerative colitis later who developed COVID-19 and was being treated with corticosteroids. The use of biologics, immunosuppressive agents, diet and personal protective provisions should be monitored and allowed to follow the strict guidelines. Previous outbreaks by members of coronaviruses, i.e., MERS and SARS, have also shown GI symptoms with higher incidence rate as compared with the SARS-CoV-2. In correspondence to SARS, the incidence of GI symptoms was 20%–38%, with one study reporting 73% incidence rate. In case of MERS, the rate of incidence of GI symptoms was 11.5%–32%.
| Mechanism of Gastrointestinal Infection in Coronavirus Disease 2019|| |
At present, there is no clarity on how and why SARS-CoV-2 induces the GI symptoms. As seen with SARS-CoV, SARS-CoV-2 also utilises the angiotensin-converting enzyme-2 (ACE-2) receptor to infect the host cells. Liang et al. investigated the location and expression of ACE-2 in humans. Their results showed that ACE-2 was found to be expressed highly in the small intestine mainly in distal and proximal enterocytes. For entry in host cells, SARS-CoV-2 not only requires ACE-2 receptor but also requires transmembrane protease serine-2 (TMPRSS-2). Zhang, et al. examined five public databases and found that TMPRSS-2 and ACE-2 were expressed in lung alveolar type 2 cells and additionally co expressed in gland cells and oesophageal upper epithelial cells. Higher expression was also seen in enterocytes from colon and ileum than in the lungs. Thus, a possibility sustains that SARS-CoV-2 might invade the ACE-2-expressing enterocytes dysregulating the intestinal processes and causing symptoms.
Other possibilities of COVID-19 causing the GI symptoms include that SARS-CoV-2 might damage the digestive tract through inflammatory response directly or indirectly. SARS-CoV-2 might affect the intestinal flora, which might affect the respiratory tract and causes alterations in the respiratory tract microbiota using immune regulation a phenomenon termed as 'gut lung axis'. Another prospect of causing the GI symptoms might be due to antibiotic-induced diarrhoea. Autopsy studies would be required to understand the SARS-CoV-2 contribution towards the digestive system. A study reported the autopsy of an 85 year old man, revealing stenosis and segmental dilatation in small intestine. This study arose a doubt regarding the secondary role of SARS-CoV-2 infection in intestine.
| Coronavirus Disease 2019 and Liver|| |
As seen with GI impacts, studies have surfaced reporting that the individuals suffering from COVID-19 may develop a varied degree of liver dysfunction. Hepatic involvements were also seen in cases of SARS and MERS. Several studies reported that individuals with COVID-19 are generally presented with abnormal levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and slightly elevated bilirubin level.,, A study describing 99 patients in Wuhan China showed 43 patients with raised AST and ALT levels and one patient had even serum AST and ALT levels raised up to 1445 U/L and 7590 U/L. The range of hepatic damage during the SARS-CoV-2 infection according to the recent findings is 14.8%–78%, as depicted in [Table 2].,,,,,,, This table also represents the range of individuals with pre-existing hepatic condition which is 2.1%–7% and is lower than the individuals with liver dysregulation throughout the course of SARS-CoV-2 infection. These results might imply that the liver injury might have been developed during the infection. A study which obtained results from post-mortem biopsies of patients who died due to COVID-19 described mild lobular and portal activity and a microvesicular steatosis stipulating that the injuries might be either drug induced or the effects of SARS-CoV-2 infection.
|Table 2: Multiple studies showing different proportions of abnormal liver profiles|
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| Mechanism of Hepatic Injury in Coronavirus Disease 2019 Patients|| |
The mechanism of hepatic injury still has less clarity. Hepatic damage during the infection may be due to virus-induced cytopathic effects, drug toxicity or an immune reaction. SARS-CoV-2 has an affinity towards ACE-2 receptor and uses the receptor to bind and enter its target cells. Data have revealed the presence of higher ACE-2-positive cholangiocytes (59.7% of the total cells) in contrast to hepatocytes (2.6% of the total cells). Binding of SARS-CoV-2 with ACE-2-positive cholangiocytes might dysregulate the liver function. A commentary also revealed that 54% of individuals infected from SARS-CoV-2 had elevated gamma-glutamyltransferase, and only 1.8% of individuals had increased levels of alkaline phosphatase. Drug-induced liver toxicity should also be investigated. It might have been caused by antipyretics, antibiotics or antiviral drugs. A study indicated that out of 12 individuals with COVID-19 in USA, 3 patients were given remdesivir at severity stage of disease, which showed an increase in liver enzymes. In addition, severely ill COVID-19 patients showed immune mediated inflammation, which may promote hepatic injury. Inflammatory response caused by inflammatory cytokine storm might cause the activation of macrophages and lymphocytes triggering them to secrete a large amount of inflammatory cytokines. During infection, lymphocytes might be essential to control the overactivated innate response. Lymphopenia throughout the infection of SARS-CoV-2 might cause a rise in cytokines such as interleukin-2 (IL-2), IL-10, IL-6 and interferon-gamma levels resulting in overactive inflammatory response causing an injury not only to pulmonary organ but also injury to the extrapulmonary sites such as liver., A study analysing the risk factors associated with the liver injury found an independent relationship between C-reactive protein levels and lymphopenia.
| Management of Coronavirus Disease 2019 Patients With Gut and Liver Problems|| |
At present, there is no specific treatment against COVID-19. Many drugs such as chloroquine, lopinavir/ritonavir, hydroxychloroquine, tocilizumab, remdesivir and aerosolised alpha-interferon are under clinical trials. GI symptoms are treated with antiemetic medications. Systemic corticosteroids are also not advised for the treatment of ARDS during SARS-CoV-2 infection. Currently, there is also no suitable vaccine for the disease.
In India, guidance has been provided by Indian National Association for the Study of the Liver, Indian Society of Gastroenterology and Society of GI Endoscopy of India for frontline workers and gastroenterologists for endoscopic procedures to be performed during this pandemic. The guidelines mainly explain regarding the limitation of staff in the procedure room, with endoscopies being done for only emergency patients. The provision of personal protective equipment by all members of the endoscopic team and pre-screening of the individual about to go under the endoscopic procedure should be mandatory. It has been reported that in 15%–54% of COVID-19 patients, elevated levels of transaminases are self-resolving. International societies such as Liver Transplant Society of India, European Association for the Study of the Liver and American Association for the Study of Liver Diseases have given the guidelines to physicians for patients with liver transplantation and chronic liver disease. As rigorous data are not yet available therefore, most of these recommendations are based on expert consensus. As SARS-CoV-2 might also infect the hepatic system, pre-screening of donors is essential. There are also concerns that immunocompromised individuals might be at a greater risk towards COVID-19 infection. There is no proof to modify the immunosuppression strategies for the transplantation patient during the pandemic, so standard immunosuppression strategies should be followed.
| Conclusion|| |
This review gives a comprehensive approach via various studies and potential pathophysiological effects with mechanism of SARS-CoV-2 related to the hepatic and GI systems. Current understanding dictates that COVID-19 might end with GI symptoms and hepatic injury by either virus-induced cytopathic effects or inflammatory response of the immune system.
Limitations and future perspectives
The limitations of this review article include that it is a narrative article rather than meta-analysis and data available related to COVID-19 gut and/or liver are scarce as COVID-19 is majorly considered to be linked with pulmonary manifestations. Moreover, to the best of our knowledge, no original work on COVID-19 and gut and/or liver has been published from India which can be considered in future. Future perspectives of COVID-19 in terms of gut and liver include questions such as the certain mechanism of induction of GI symptoms, possible faecal-oral transmission, doubts regarding the liver injury and significance of viral detection in stool specimens. Further research and clinical studies are required to define a more robust guideline on COVID-19 infection, which might be a necessary tool in this fight against SARS-CoV-2.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Singhal T. A review of coronavirus disease-2019 (COVID-19). Indian J Pediatr 2020;87:281-6.
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;382:1708-20.
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.
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.
Musa S. Hepatic and gastrointestinal involvement in coronavirus disease 2019 (COVID-19): What do we know till now? Arab J Gastroenterol 2020;21:3-8.
Wong SH, Lui RN, Sung JJ. Covid-19 and the digestive system. J Gastroenterol and Hepatol 2020;35:744-8.
Cai Q, Huang D, Ou P, Yu H, Zhu Z, Xia Z, Su Y, et al
. COVID-19 in a designated infectious diseases hospital outside Hubei Province, China. Allergy 2020;00:1-11.
Fan Z, Chen L, Li J, Cheng X, Yang J, Tian C, et al
. Clinical features of COVID-19-related liver damage. Clin Gastroenterol Hepatol 2020;18:1561-6.
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;8:475-81.
Zhang JJ, Dong X, Cao YY, Yuan YD, Yang YB, Yan YQ, et al
. Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan, China. Allergy 2020:1-12. [published online ahead of print].
Jin X, Lian JS, Hu JH, Gao J, Zheng L, Zhang YM, et al
. Epidemiological, clinical and virological characteristics of 74 cases of coronavirus-infected disease 2019 (COVID-19) with gastrointestinal symptoms. Gut 2020;69:1002-9.
Lin L, Jiang X, Zhang Z, Huang S, Zhang Z, Fang Z, et al
. Gastrointestinal symptoms of 95 cases with SARS-CoV-2 infection. Gut 2020;69:997-1001.
Holshue ML, DeBolt C, Lindquist S, Lofy KH, Wiesman J, Bruce H, et al
. First case of 2019 novel coronavirus in the United States. N
Engl J Med 2020;382:929-36.
Patel KP, Patel PA, Vunnam RR, Hewlett AT, Jain R, Jing R, et al
. Gastrointestinal, hepatobiliary, and pancreatic manifestations of COVID 19. J Clin Virol 2020;128:1-5.
Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H. Evidence for gastrointestinal infection of SARS-CoV-2. Gastroenterology 2020;158:1831-3000.
Zhang J, Wang S, Xue Y. Fecal specimen diagnosis 2019 novel coronavirus-infected pneumonia. J Med Virol 2020;92:680-2.
Young BE, Ong SWX, Kalimuddin S, Low JG, Tan SY, Loh J, et al
. Epidemiologic features and clinical course of patients infected with SARS-CoV-2 in singapore. JAMA 2020;323:1488-94.
Lu X, Zhang L, Du H, Zhang J, Li YY, Qu J, et al
. SARS-CoV-2 Infection in Children. N
Engl J Med 2020;382:1663-5.
Xu Y, Li X, Zhu B, Liang H, Fang C, Gong Y, et al
. Characteristics of pediatric SARS-CoV-2 infection and potential evidence for persistent fecal viral shedding. Nat Med 2020;26:502-5.
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.
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;323:1061-9.
Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, et al
. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020;133:1025-31.
Pan L, Mu M, Yang P, Sun Y, Wang R, Yan J, et al
. Clinical Characteristics of COVID-19 Patients With Digestive Symptoms in Hubei, China: A Descriptive, Cross-Sectional, Multicenter Study. Am J Gastroenterol 2020;115:766-73.
Mazza S, Sorce A, Peyvandi F, Vecchi M, Caprioli F. A fatal case of COVID-19 pneumonia occurring in a patient with severe acute ulcerative colitis. Gut 2020;69:1148-9.
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;69:1141-3.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger 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;181:271-800.
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.
Li L, Li S, Xu M, Yu P, Zheng S, Duan Z, et al
. Risk factors related to hepatic injury in patients with corona virus disease 2019. medRxiv 2020.
Zhang B, Zhou X, Qiu Y, Feng F, Feng J, Jia Y, et al
. Clinical characteristics of 82 death cases with COVID-19. medRxiv 2020.
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.
Chai X, Hu L, Zhang Y, Han W, Lu Z, Ke A, et al
. Specific ACE2 expression in cholangiocytes may cause liver damage after 2019- nCoV infection. BioRxiv 2020.
Kujawski SA, Wong KK, Collins JP, Epstein L, Killerby ME, Midgley CM, et al
. Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nature Med 2020;26:861-8.
Liu J, Li S, Liu J, Liang B, Wang X, Wang H, et al
. Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients. EBioMedicine 2020;55:102763.
Philip M, Lakhtakia S, Aggarwal R, Madan K, Saraswat V, Makharia G. Joint Guidance from SGEI, ISG and INASL for Gastroenterologists and Gastrointestinal Endoscopists on the Prevention, Care, and Management of Patients With COVID-19. J Clin Exp Hepatol 2020;10:266-70.
Bollipo S, Kapuria D, Rabiee A, Ben-Yakov G, Lui RN, Lee HW, et al
. One world, one pandemic, many guidelines: Management of liver diseases during COVID-19. Gut 2020.
[Table 1], [Table 2]