Revista da Sociedade Brasileira de Medicina Tropical

Journal of the Brazilian Society of Tropical Medicine

Vol.:53:(e20200714): 2020
https://doi.org/10.1590/0037-8682-0714-2020

Major Article

COVID-19 gastrointestinal manifestations:

a systematic review
Filipe Antônio França da Silva[1], Breno Bittencourt de Brito[1],
Maria Luísa Cordeiro Santos[1], Hanna Santos Marques[2], Ronaldo Teixeira da Silva Júnior[1],
Lorena Sousa de Carvalho[1], Elise Santos Vieira[1],
Márcio Vasconcelos Oliveira[1] and Fabrício Freire de Melo[1]

[1]. Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Vitória da Conquista, BA, Brasil.
[2]. Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista, BA, Brasil.

Abstract
Introduction: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has greatly
challenged public health worldwide. A growing number of studies have reported gastrointestinal (GI) symptoms. We performed a
systematic review of GI symptoms associated with coronavirus disease 2019 (COVID-19) as well as of the serum levels of biomarkers
related to liver function and lesion in SARS-CoV-2-infected individuals. Methods: We surveyed relevant articles published in English,
Spanish, and Portuguese up to July, 2020 in the PubMed, MEDLINE, SciELO, LILACS, and BVS databases. Moreover, we surveyed
potentially important articles in journals such as the NEJM, JAMA, BMJ, Gut, and AJG. Results: This systematic review included 43
studies, including 18,246 patients. Diarrhea was the most common GI symptom, affecting 11.5% of the patients, followed by nausea
and vomiting (6.3%) and abdominal pain (2.3%). With regard to clinical severity, 17.5% of the patients were classified as severely ill,
whereas 9.8% of them were considered to have a non-severe disease. Some studies showed increased aspartate transaminase and alanine
aminotransferase levels in a portion of the 209 analyzed patients and two studies. Conclusions: Our results suggest that digestive
symptoms are common in COVID-19 patients. In addition, alterations in cytolysis biomarkers could also be observed in a lesser
proportion, calling attention to the possibility of hepatic involvement in SARS-CoV-2-infected individuals.
Keywords: COVID-19. SARS-CoV-2. Gastrointestinal manifestation. Gastrointestinal symptom. Systematic review.

INTRODUCTION commonly reported, while taste and olfactory disorders are more
common when associated with other manifestations6,7. Interestingly,
Respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
a study published in January, 2020 reported a patient with diarrhea
was first reported as a viral pneumonia outbreak in Wuhan, China,
as a gastrointestinal (GI) manifestation of SARS-CoV-2 infection.
in December 2019, and its rapid spread has become a public
Since then, several cases reporting COVID-19 along with GI
health challenge1,2. The potentially fatal coronavirus disease 2019
symptoms such as diarrhea, nausea, vomiting, abdominal pain,
(COVID-19) has evolved to a pandemic affecting all continents,
anorexia, and GI bleeding have been described8. Among the GI
except for Antarctica2,3. As at July 30, 2020, more than 16,812,763
symptoms that have been described in adult COVID-19 patients,
cases and 662,095 deaths have been reported globally according to the
the most common are diarrhea, followed by nausea/vomiting and
World Health Organization (WHO)4. SARS-CoV-2 is an infectious
abdominal pain, while in pediatric patients, vomiting is more
agent associated with a large-spectrum clinical presentation5, which
frequently reported3,9. In addition, studies have shown severe cases
classically involves respiratory tract symptoms such as fever,
with the presence of SARS-CoV-2 RNA in esophageal ulcers as well
dry cough, and shortness of breath. Myalgia and fatigue are also
as in stomach, duodenum, and rectal tissues of these patients10. It
was also observed that patients with severe disease are more likely to
Corresponding author: Fabrício Freire de Melo.
have abdominal pain when compared to non-severe patients as well
e-mail: freiremelo@yahoo.com.br
 https://orcid.org/0000-0002-5680-2753 as a greater chance of having abnormal serum levels of biomarkers
Received 21 October 2020 related to liver function and lesion, associated with GI involvement
Accepted 4 November 2020 and worse disease prognosis11,12. Studies have suggested that the

www.scielo.br/rsbmt I www.rsbmt.org.br 1/11

França da Silva FA et al. - COVID-19 gastrointestinal manifestations

angiotensin-converting enzyme II (ACE2) receptor, which mediates Study Selection: The eligibility of the articles was evaluated
SARS-CoV-2 infection, is expressed in lung AT2 cells as well as in by three independent reviewers (Da Silva, FAF; Santos, MLC;
the esophagus upper and stratified epithelial cells and absorptive and Marques, HS). Duplicated articles were excluded. The titles
enterocytes from the ileum and colon. These findings may be and abstracts of the articles were evaluated, and studies that did
associated with GI manifestations11,13. Moreover, SARS-CoV-2 not fit the inclusion criteria were excluded. A fourth reviewer (de
RNA has been identified in stool specimens and anal or rectal swabs Melo, FF) resolved any disagreements between the three reviewers.
of COVID-19 patients14. Notably, some data indicate that the viral In order to verify if the articles met all previously established
RNA may remain detectable in the stool even after negative results criteria, each article was individually analyzed.
from respiratory samples15,16. Therefore, fecal-oral transmission may
be another possible SARS-CoV-2 transmission route, and should Data Collection Process: We developed a structured
be considered in infection control measures17. In this systematic data extraction spreadsheet specifically for this review based
review, we analyzed the current international evidence regarding on the criteria recommended by the Cochrane Handbook of
the association between the GI tract and COVID-19. Systematic Reviews for Interventions 19. We independently
reviewed the relevant study data and results of interest such as GI
METHODS
symptoms and biomarkers related to liver function and lesion in
The criteria recommended by the preferred reporting items for COVID-19 patients.
systematic reviews and meta-analyses (PRISMA) checklist were
Data items: Information was extracted from each study and
followed to conduct this systematic review18.
stratified into (1) general epidemiologic and clinical characteristics
Eligibility Criteria of participants and studies; (2) diarrhea; (3) nausea; (4) vomiting;
(5) abdominal pain; (6) any GI symptom; (7) severity of COVID-19
Types of participants: Adults and children diagnosed
infection; and (8) biomarkers related to liver function and lesion:
with SARS-CoV-2 infection confirmed by real-time reverse
albumin, prothrombin time, aspartate aminotransferase, and alanine
transcriptase-polymerase chain reaction (RT-PCR), who had
aminotransferase.
concomitant GI symptoms.
Assessment of quality of studies: To assess of the quality of the
Types of study: Prospective and retrospective studies
published in peer-reviewed journals up to July, 2020 that reported 43 selected studies, National Institute of Health (NIH/NHLBI) tools,
epidemiological and clinical data of patients with COVID-19, the which were developed through a collaboration with the National
prevalence of GI symptoms, and the serum levels of biomarkers Heart, Lung, and Blood Institute (NHLBI) and the Research
related to liver function and injury in these patients were included. Triangle Institute International, were used20. To comply with the aim
The following studies were excluded: studies that did not report GI of this systematic review, the NIH tool for case series was applied in
symptoms, duplicated studies, studies that included patients infected 33 studies. It uses nine domains, including the presence of a clearly
with other coronavirus types, case reports, reviews, meta-analyses, defined objective and well-described results. Based on that, each
systematic reviews, editorials, small case series (< 15 cases), and case series received a general classification as long as it received a
clinical trials evaluating medications. Studies that did not have a “yes” in each domain. Good, regular, and bad studies had positive
complete version published as a free full text were excluded. Studies results in ≥ 6 domains, 3–5 domains, and < 3, respectively. For nine
published in English, Spanish, and Portuguese were included. studies, the NIH tool for observational cohort and cross-sectional
studies was used, which features fourteen domains. Therefore,
Types of outcome measures: We collected data evaluating the
good, regular, and bad studies obtained “yes” in ≥ 9 domains, 5–8
occurrence of GI symptoms caused by COVID-19 and the serum
domains, and ≤ 4 domains, respectively. One study was assessed
levels of biomarkers related to liver function and lesion.
using the NIH tool for case-control studies, which uses twelve
Information sources: We surveyed the relevant articles domains, and good, regular, and bad studies obtained “yes” in ≥ 8
published in English, Spanish, and Portuguese up to July, 2020 in domains, 5–7 domains, and ≤ 4 domains, respectively.
the United States National Library of Medicine (PubMed), Medical
RESULTS
Literature Analysis and Retrieval System Online (MEDLINE),
Scientific Electronic Library Online (SciELO), Latin American Study Selection
Literature in Health Sciences (LILACS), and Virtual Health Library
(BVS) databases. The search terms used for all databases were: A total of 3,850 articles were identified in our searches. We
(Coronavirus [OR] severe acute respiratory syndrome coronavirus excluded 28 duplicate articles, and 3,821 remained. A further 3,754
2 [OR] SARS-CoV-2 [OR] COVID-19 [and] gastrointestinal studies were removed after reviewing the titles and abstracts. The
symptoms [OR] clinical features [OR] clinical manifestations). Due remaining 68 articles were assessed for eligibility, of which 25
to a large number of publications on the topic and their urgency were excluded because of the following reasons: three were case
and importance, we also surveyed potentially important articles reports; three studies reported COVID-19 cases without RT-PCR
published in the New England Journal of Medicine (NEJM), confirmation; four articles had insufficient data; and 15 studies had
the Journal of the American Medical Association (JAMA), the no patients experiencing GI symptoms. Finally, 43 studies were
British Medical Journal (BMJ), Gastroenterology, Gut, and the included. Figure 1 shows the selection and distribution of articles
American Journal of Gastroenterology (AJG) in order to increase according to the databases searched from the first search to the
the sensitivity of the research. application of all the selection criteria.

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FIGURE 1: Summary of study selection process.

Study characteristics percentage did not undergo a substantial change (52.1%) when articles
that exclusively reported COVID-19 patients with GI symptoms
The characteristics of the 43 studies selected are summarized were included, and a total of 4,614 patients in eight studies were
in Table 1. A total of 18,246 patients, of all age ranges, were separately analysed31-35,51,52,54. Diarrhea was the most commonly
included. Most studies were retrospective. Regarding the geographic reported symptom, being detectable in 11.5% (n = 2115) of patients
distribution of the studies, 69% of the articles were from China, 16% (38 articles), followed by nausea and vomiting, reported in 6.3%
were from the USA, 7% were from Poland, and 2% were from Italy, (n = 1158) of participants (31 studies), and abdominal pain, found
Chile, Spain, and Korea. Figure 2 shows the geographic distribution in 2.3% (n = 424) of the individuals (21 studies). In 21 studies, the
of the studies. In addition, the articles included had several aims, presence of any GI manifestations showed a prevalence of 30.5%
such as evaluating epidemiological characteristics, imaging, and (n = 1841) (Figure 3). In addition to the symptoms shown in Table 1,
clinical features, in addition to assessing the occurrence of GI loss of appetite, anosmia, ageusia, and intestinal bleeding were reported.
symptoms in patients infected with SARS-CoV-2.
Subgroup analyses
GI manifestations
In order to examine the possible relationship between the
All 43 articles analyzed reported at least one GI symptom in presence of GI symptoms and COVID-19 severity, we analyzed the
COVID-19 patients. There was no relevant difference in the number illness seriousness of the patients present in the 43 articles included.
of patients between sexes (50.5% of the individuals were men). That Among them, 14 studies, shown in Table 1, stratified patients as

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TABLE 1: Epidemiological and clinical data of positive COVID-19 patients.

Patients
Country / Adult / Children / Woman / Severe / Non with any GI Diarrhea Nausea / Abdominal
N Author Study design N
Year Median Age Man (N) Severe (N) symptom (N) vomiting (N) pain
(N)

1 Chen, et al.21 China - 2020 RS 21 Adult: 61 years 4/17 11/10 NR 4 NR NR

2 Xu, et al.22 China - 2020 RS 90 Adult: 50 years 51/39 NR NR 5 7 NR

3 Li, et al.23 China - 2020 RS 83 Adult: 45.5 years 39/44 58/25 7 NR NR NR

4 Yang W, et al.24 China - 2020 RS 149 Adult: 45.11 years 68/81 NR NR 11 2 NR

5 Liu, et al.25 China - 2020 RS 137 Adult: 57 years 76/61 NR NR 11 NR NR

6 Wu, et al.26 China - 2020 RS 80 Adult: 44 years 38/42 NR 7 NR NR NR

7 Liang, et al.27 China - 2020 RS 1590 Adult: 48.9 years 674/904 131/- NR 57 80 NR

8 Zheng, et al.28 China - 2020 RS 25 Children: 3 years 11/14 2/23 NR 3 2 2

9 Lokken, et al.29 USA - 2020 RS 46 Adult: 29 years 46/0 NR NR 3 5 NR

10 Wang, et al.30 China - 2020 RS 275 Children/Adult: 49 years 147/128 45/230 NR 7 8 NR

11 Jin, et al.31 China - 2020 PS 651 Adult: 46.14 years 320/331 64/- 74 53 21 NR

12 Lin, et al.32 China - 2020 PS 95 Adult: 45.3 years 50/45 20/75 23 23 21 NR

13 Redd., et al.33 USA - 2020 PS 318 Adult: 63.4 years 144/174 NR 195 107 133 46

14 Sierpiński, et al.34 Poland - 2020 RS 1942 Adult: 50 years 1169/773 NR 912 470 NR NR

15 Luo, et al.35 China - 2020 RS 1141 Adult: 53.8 years NR NR 263 68 253 45

16 Liu BM, et al.36 China - 2020 RS 68 Adult: 44.3 years 43/25 NR NR 5 4 NR

17 Li, et al.37 China - 2020 RS 70 Adult: 44.6 years 23/43 NR 2 2 2 0

18 Yin, et al.38 China - 2020 RS 33 Adult: 46 years 17/16 NR NR 5 NR NR

19 Derespina, et al.39 USA- 2020 RS 70 Children: 15 years 27/42 NR NR 18 24 NR

20 Xiong, et al.40 China - 2020 PS 244 Children: 1.2 years 94/150 11/- 8 15 23 4

21 Pan, et al.41 China - 2020 RS 204 Adult: 52.9 years 97/107 NR 81 35 4 2

22 Du, et al.42 China - 2020 RS 182 Children: 6 years 62/120 4/- 20 9 7 7

23 Rivera, et al.43 Spain - 2020 RS 76 Adult: 45.8 years 53/23 NR 57 31 24 21

24 Zhang, et al.44 China - 2020 RS 140 Adult: 57 years 69/71 11/31 8 NR NR NR

25 Kim, et al.45 Korea -2020 RS 28 Adult: 40 years 13/15 NR 3 3 1 1

26 Zhao, et al.46 China - 2020 RS 101 Adult: 44 years 45/56 14/- 5 3 2 NR

27 Xu, et al.47 China - 2020 RS 62 Adult: 41 years 27/35 NR 5 3 NR NR

Continue...

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TABLE 1: Continuation.

Patients
Country / Adult / Children / Woman / Severe / Non with any GI Diarrhea Nausea / Abdominal
N Author Study design N
Year Median Age Man (N) Severe (N) symptom (N) vomiting (N) pain
(N)

28 Yang, et al.48 USA- 2020 RS 124 Adult: 75.7 years 66/58 NR NR 9 14 NR

29 Suleyman, et al.49 USA- 2020 RS 463 Adult: 57.5 years 259/204 NR NR 100 147 NR

30 Chen, et al.50 China - 2020 RS 175 Adult: 45 years 87/88 40/- NR 35 7 5

31 Cholankeril, et al.51 USA -2020 RS 116 Adults: 50 years 54/62 NR 59 12 12 10

32 Nobel YR, et al.52 USA -2020 RS 278 NR 133/145 NR 97 56 63 NR

33 Wei, et al.53 China - 2020 RS 84 Adults: 37 years 56/28 NR 4 26 22 2

34 Xiao F, et al.54 China - 2020 PS 73 Adults: 43 years 32/41 NR 10 26 NR NR

260
35 Díaz LA, et al.55 Chile - 2020 PS 7016 Adults: 39.7 years 3508/3508 NR NR 511 NR

36 Chen T, et al.56 China - 2020 RS 274 Adults: 62 years 103/171 274/- NR 77 40 19

37 Argenziano et al.57 USA - 2020 RS 1000 Adults: 63 years 404/596 NR NR 236 178 NR

38 Zheng, et al.58 China - 2020 RS 52 Children: 9 years 24/28 NR 1 NR NR NR

39 Garazzino, et al.59 Italian - 2020 RS 168 Children: 5.2 years 74/94 NR NR 22 9 NR

40 Wang, et al.60 China - 2020 RS 125 Adult: 38.76 years 54/71 NR NR 50 24 NR

41 Du, et al.61 China - 2020 RS 67 Children/Adult: 34.10 years 35/32 NR NR 2 4 0

42 Nowak, et al.62 Poland- 2020 RS 169 Adult: 63.7 years 82/87 NR NR 8 6 NR

43 Chen, et al.63 China - 2020 RS 141 Adult: 47.3 years 68/73 15/- NR 5 9 NR

RS: Retrospective study; PS: Prospective study; NR: not reported; GI: gastrointestinal.

FIGURE 2: Geographical distribution of the studies.

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FIGURE 3: Scatter plot of gastrointestinal symptoms in patients with COVID-19.

Legend: Graph showing the number of COVID-19 positive patients and the gastrointestinal symptoms seen in
18,246 analyzed patients.

severe/critical or not severely ill. A total of 17.5% (700) of the DISCUSSION

patients were considered to have severe COVID-19, whereas 9.8%
Since the first infection cases reported in December 2019, SARS-
(394) had a non-severe illness. We also observed that the average
CoV-2 has spread worldwide and, subsequently, COVID-19 was declared
age among severely ill adults ranged from 44 to 62 years, whereas
a pandemic by the World Health Organization64,65. Therefore, a large
the mean age among children who experienced severe disease
number of studies have been published by the scientific community
ranged from 1.2 to 6 years.
in a short period of time in order to understand the mechanisms of
Liver function and injury this new virus and to research possible treatments and vaccines.
Among the 43 studies included in the final analysis, 24 evaluated The most commonly reported symptoms in clinical and
biomarkers related to liver function and injury; however, we only epidemiological studies involving COVID-19 patients are fever,
analyzed articles that assessed those biomarkers in COVID-19 dry cough, and dyspnea25-27. However, a growing number of studies
patients with GI symptoms. In this regard, we included data from have reported a series of GI symptoms in these patients due to the
seven articles with a total of 665 patients (Table 2), from which involvement of the GI system in the pathophysiology of the COVID-19.
two studies with 209 patients reported mild increases in the mean Diarrhea
aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) serum levels35,51. All of the articles included in this systematic review reported
Assessment of quality of studies patients with diarrhea. Among the studies, 39 provided the number
of patients who had that symptom, as shown in Table 1, whereas
The quality of the studies was assessed using NIH tools for case four articles did not provide its prevalence23,26,44,58. Our results
series20 in 33 studies, and the results are shown in Figure 4. The demonstrate that diarrhea is the most common GI symptom in
scores were: 8/9 for 7 studies (22%), 7/9 for 11 studies (33%), 6/9 SARS-CoV-2 infection, in agreement with a prior meta-analysis that
for 9 studies (27%), and 5/9 for 6 studies (18%). Thus, 27 studies evaluated 26 studies and 4,676 patients66. Among the individuals
(82%) were of good quality (score ≥ 6), 6 studies (18%) of regular sampled in the present review, 2,115 (11.5%) manifested diarrhea
quality (score 3–5), and no study was found to be of poor quality. during SARS-CoV-2 infection. A similar prevalence (10.3%) was
Nine studies30,33,34,39,45,48,50,51,55 included in this systematic review were reported by Cholankeril et al. (2020)51 in an American study that
analyzed using NIH tools for observational cohort and cross-sectional evaluated 116 patients. In this systematic review, the prevalence of
studies20. The scores were as follows: 10/14 for two studies (22.2%), diarrhea ranged from 2.8%37 to 40.7%43 among studies assessing
9/14 for two studies (22.2%), 8/14 for one study (11.2 %), 7/14 for general epidemiological and clinical characteristics of COVID-19
three studies (33.2%), and 6/14 for one study (11.2%). Thus, four patients. On the other hand, the percentage of individuals who
studies (44,4 %) had a good quality (score ≥ 9) and 5 studies (55.6 experienced symptoms varied from 5.95%35 to 35.6%54 in studies
%) had regular quality (score 5–8). The case-control study52 included that only included patients with GI symptoms during SARS-
was analyzed according to NIH tools for case-control studies20 and CoV-2 infection. With regard to the diarrhea duration, Jin et al.
obtained a 7/12 score, which was considered as a regular-quality study. reported an average period of 4 days in 53 patients, ranging from

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TABLE 2: Data on the serum level of biomarkers related to liver function and injury in patients with COVID-19.

Author N AST (IU/L) ALT (IU/L) Albumin (g/L) Prothrombin time (s)

Value P Value P Value P Value P

Jin, et al.31 74 29.35 0.02 25.0 0.203 40.13 0.039 NR NR
Lin, et al.32 58 17.6 ± 5.6 NR 22.5 ± 19.2 NR NR NR NR NR
Redd, et al.33 195 46.7 ± 35.3 0.26 35.9 ± 31.8 0.97 NR NR 35.8 ± 11.6 0.52
Luo, et al.35 183 65.8 ± 12.7 NR 66.4 ± 13.2 NR NR NR NR NR
Pan, et al.41 103 35.12 ± 6.58 0.032 42.24 ± 43.83 0.011 36.16 ± 6.49 0.707 13.13 ± 1.88 0.024
Cholankeril, et al.51 26 64 0.009 59 0.009 NR NR NR NR
Wei, et al. 53
26 24.9 ± 6.4 0.055 20.6 ± 7.5 0.014 40.5 ± 4.7 0..837 13.8 ± 2.6 0.051

AST range = 15–40 IU/L; ALT range = 9–50 IU/L; albumin range= 40–55 g/L; prothrombin time range= 11–13.5 s.

FIGURE 4: Quality analysis chart of included studies.

1 to 9 days, with a self-limited course. Some authors have studied Table 1. These data are similar to the results of Chen et al. (2020)21
the relationship between GI symptoms and ACE2 expressed and Liang et al. (2020)27 who demonstrated a prevalence of nausea
on AT2 cells of the GI system, which may allow SARS-CoV-2 and/or vomiting of 6.3% (9/141) and 5% (80/1590), respectively. In a
infection11,13,67. Adding to this knowledge, in a meta-analysis relevant review that included 2,023 patients, it was observed that the
that included 4,243 patients with COVID-19 and GI symptoms, presence of vomiting was more common in children than in adults,
SARS-CoV-2 RNA was detected in stool samples of 48.1% with 6.5%–66.7% and 3.6%–15.9% prevalence ranges, respectively9.
(95% confidence interval [CI]: 6.9–36.7) of the participants68. This phenomenon was verified by our review, since Lokken et al.
Moreover, it should be emphasized that some authors reported that (2020)29 and Argenziano et al. (2020)57 reported nausea and/or vomiting
the first COVID-19 symptom can be a GI presentation, as observed prevalence rates of 10.8% and 17.8% in an adult population, whereas
in eight patients from a relevant study who had fever and diarrhea Redd et al. (2020)33 and Derespina et al. (2020)39 found these symptoms
before the onset of respiratory manifestations69. Therefore, health in 41.8% and 34.2% of SARS-CoV-2-infected children, respectively.
professionals should not rule out a COVID-19 diagnosis in patients
Abdominal pain
with diarrhea in geographical areas with SARS-CoV-2 circulation.
Nausea and vomiting The prevalence of abdominal pain in our analysis was 2.3%
(424) in 21 studies. In a meta-analysis comprising 4,243 patients,
Our analyses showed that 1,158 (6.3%) of the patients presented it was observed that 17.1% of the patients with severe COVID-19
with nausea and/or vomiting in 31 studies, as described in had GI symptoms (95% CI = 6.9–36.7)68. Interestingly, another

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meta-analysis observed that critically ill COVID-19 patients ARTICLE HIGHLIGHTS

have significantly higher odds of experiencing abdominal pain
when compared to not severely ill patients (OR = 7.17, 95% CI = Research background
1.95–26.34, P = 0.003), and that symptoms may be a predictor of
The pandemic caused by severe acute respiratory syndrome
unfavorable outcomes11. In order to increase the level of evidence
coronavirus 2 (SARS-CoV-2) infection has greatly challenged
on the relationship between abdominal pain and SARS-CoV-2
infection prognosis, further studies should be performed. public health worldwide. COVID-19 is currently described as a
disease with a broad spectrum of symptoms, the most prevalent
Liver function and damage being dry cough, fever, and shortness of breath. However, a
In our results, seven authors evaluated biomarkers related to growing number of studies have reported GI symptoms such as
liver function and damage in patients with COVID-19 and GI diarrhea, nausea, vomiting, abdominal pain, anorexia, and GI
symptoms (Table 2). However, only the studies by Luo et al. bleeding, calling attention to the importance of this set of clinical
(2019)35 and Cholankeril et al. (2020)51 reported abnormal AST manifestations among infected individuals.
and ALT averages. The latter observed an association between Research motivation
the severity of the disease and AST levels (Pearson’ s coefficient
= 0.33; P = 0.009). In a Chinese meta-analysis of 6,686 patients, SARS-CoV-2 has spread worldwide, and as at the last week of
a significant increase was observed in both ALT (OR = 1.89, 95% July 2020, more than 16 million cases and 662 thousand deaths have
CI = 1.30–2.76, P = 0.0009) and AST (OR = 3.08, 95% CI = 2.14– been reported globally. In this scenario, it is important to identify
4.42, P < 0.00001) levels among severely ill patients than in non- the diversity of clinical manifestations of COVID-19, understanding
severely ill individuals70. In addition, an interesting meta-analysis the different ways through which patients can be affected. In this
from Canada with 3,615 adult patients diagnosed with COVID-19 sense, understanding the association between COVID-19 and GI
from 15 studies noted that acute liver injury was associated with symptoms is crucial.
increased mortality (RR = 4.02 [1.51, 10.68], P = 0.005)71. Liver
Research objectives
abnormalities and the subsequent increase in the circulating levels
of cytolysis biomarkers in patients with COVID-19 may be caused To perform a systematic review of the GI symptoms and serum
by the infection-associated inflammatory storm, hepatic ischemia, levels of cytolysis biomarkers related to liver function and injury
reperfusion dysfunction, or drug toxicity72. In fact, AST has been among COVID-19 patients.
considered as a hepatic marker of COVID-19 severity; however,
we understand that such enzymes have high activities in the liver, Research methods
heart, and muscles, in addition to minimal activity in the kidney
A systematic review of the current literature as at July, 2020
and pancreas. In view of the association of SARS-CoV-2 with
was performed according to the PRISMA statement. During the
extrapulmonary manifestations such as cardiac repercussions73,
screening process, articles that were not published in English,
for example, the increase in AST rates may not be such a sensitive Portuguese, or Spanish as well as unavailable reports and single
marker for liver injury in this context. ALT also plays a role in case reports were excluded. The search was performed using
various organic systems; nonetheless, it has the greatest activity a combination of the terms Coronavirus [OR] severe acute
in the liver74. A remarkable study on liver enzymes concluded that respiratory syndrome coronavirus 2 [OR] SARS-CoV-2 [OR]
restricting the biological role of these enzymes to liver damage is an COVID-19 [and] gastrointestinal symptoms [OR] clinical features
underestimated interpretation of these biomarkers75. In addition to [OR] clinical manifestations. The databases selected for this
liver injury biomarkers, work should begin to further analyze liver review were PubMed, MEDLINE, SciELO, LILACS, and BVS.
function biomarkers to build a global view of the consequences of Potentially important articles published in NEJM, JAMA, BMJ,
SARS-CoV-2 infection at the liver level. Gastroenterology, Gut, and AJG were also selected.
Study limitations Research results

We aimed to limit publication bias by including studies This systematic review included 43 studies, including 18,246
published in languages other than English. However, this systematic patients. There was no significant difference between the number
review has some limitations. First, this study was mostly a of male (50.5%) and female (49.5%) participants. Individuals of
compound of retrospective studies. Moreover, there is a potential all age groups were included. At least one patient in each study
risk of heterogeneity and publication bias with regard to COVID-19 included had GI symptoms associated with COVID-19, and the
patients with GI symptoms, as well as to the disease severity criteria prevalence of such symptoms was similar among men and women
used by the authors. (52.1% and 49.5%, respectively). Diarrhea was the most common
GI symptom, affecting 11.5% of the patients, followed by nausea
In conclusion, our results suggest that digestive symptoms are and vomiting (6.3%) and abdominal pain (2.3%). Loss of appetite,
common in COVID-19 patients. In addition, alterations in cytolysis anosmia, ageusia, and GI bleeding were also reported. With regard
biomarkers could also be observed in a lesser proportion, calling to clinical severity, 17.5% of the patients were classified as severely
attention to the possibility of hepatic involvement in SARS-CoV-2- ill, whereas 9.8% of them were considered to have a non-severe
infected individuals. disease. Moreover, the mean age of severely ill patients ranged from

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44 to 62 years in adults and from 1.2 to six years among children. 5. Coronaviridae Study Group of the International Committee on
Some studies evaluated cytolysis biomarkers in COVID-19 patients Taxonomy of Viruses. The species Severe acute respiratory syndrome-
related coronavirus: classifying 2019-nCoV and naming it SARS-
who had GI symptoms, showing increased aspartate transaminase
CoV-2. Nat Microbiol. 2020;5(4):536-44.
and alanine aminotransferase levels in a portion of the 209 analyzed
patients and two studies. 6. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott
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The authors declare that there is no conflict of interest.
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