Introduction

F1000Research

2046-1402

F1000 Research Limited

London, UK

10.12688/f1000research.134938.1

Systematic Review

Articles

Prognostic role of C-reactive protein-to-albumin ratio in acute pancreatitis: a systematic review and meta-analysis

[version 1; peer review: 2 approved with reservations]

Mariadi

I Ketut

Conceptualization Formal Analysis Methodology Supervision Validation Writing – Review & Editing https://orcid.org/0000-0001-9665-8082 a 1 Somayana

Gde

Conceptualization Investigation Methodology Supervision Validation Writing – Review & Editing 1 Shalim

Christina Permata

Data Curation Investigation Methodology Writing – Original Draft Preparation https://orcid.org/0000-0002-1853-3310 2 Sindhughosa

Dwijo Anargha

Conceptualization Supervision Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0003-4933-9446 1 Daniella

Dian

Investigation Writing – Review & Editing https://orcid.org/0000-0001-8698-1265 3 Purwanta

Made Lady Adelaida

Investigation Writing – Review & Editing 4 1Division of Gastroenterology and Hepatology, Faculty of Medicine, Udayana University/Prof Dr. I.G.N.G. Ngoerah Hospital, Denpasar, Bali, Indonesia 2Siloam Hospitals Kebon Jeruk, West Jakarta, Jakarta, Indonesia 3Department of Internal Medicine, Faculty of Medicine, Udayana University/Prof Dr. I.G.N.G. Ngoerah Hospital, Denpasar, Bali, Indonesia 4Intern Doctor, Internal Medicine Department, Bali Mandara Hospital, Denpasar, Bali, Indonesia

a mariadi@unud.ac.id

No competing interests were disclosed.

26 6 2023

2023

748

7 6 2023

2023

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background: Acute pancreatitis (AP) is a common disorder and although most of the cases are mild, the mortality risk is high when it comes to severe AP. It is therefore important to determine the severity of AP as early as possible. This review aimed to determine the prognostic value of C-reactive protein-to-albumin ratio (CRP/alb ratio) in patients with AP.

Methods: We performed a systematic search on the electronic databases PubMed, Cochrane Library, and Google Scholar up to January 2023. Studies reporting CRP/alb ratio on admission and its association with severity or mortality in AP patients were included. We calculated pooled mean difference (MD) and their 95% confidence intervals (CI) using a random-effects model. Quality assessment of the included studies was appraised using a Newcastle–Ottawa scale.

Results: A total of six studies comprising 2244 patients were included in this meta-analysis. Severe AP had higher CRP/alb ratio on admission than mild-moderate AP (pooled MD: 3.59; 95% CI: 2.51-4.68; p<0.00001). CRP/alb ratio was also significantly higher on non-survivor AP patients compared to survivor AP patients (pooled MD: 2.12; 95% CI: 0.43-3.8; p < 0.01).

Conclusion: High CRP/alb ratio can be used as an early predictor of poor prognosis in patients with AP.

c-reactive protein albumin acute pancreatitis prognostic meta-analysis

The author(s) declared that no grants were involved in supporting this work.

Introduction

Acute pancreatitis (AP) is an inflammation of the pancreas characterized by sudden and severe onset of abdominal pain and elevated pancreatic enzyme. ¹ ^, ² This condition is mostly caused by bile stones or heavy use of alcohol. Even though most of the cases are mild, the mortality risk is high when it comes to severe AP. The overall mortality rate of AP is 3% to 10%, but in severe AP the mortality rate rises to 36% to 50%. ³ Thus, early determination of the disease severity to choose appropriate therapeutic strategy are of great importance.

Several scoring systems are commonly used to determine the severity and prognosis of AP, such as Ranson scores, bedside index for severity in acute pancreatitis (BISAP), acute physiological assessment and chronic health evaluation II (APACHE II), and Atlanta classification. ⁴ These scoring systems use multiple blood test results and clinical parameters, and almost all of them need repeated blood tests 48 hours after admission to increase its accuracy on predicting AP severity. There is a need for tools to predict the prognosis of AP within the first hour of admission.

C-reactive protein (CRP) is an inflammatory marker that is widely used in clinical practice to determine the severity of various inflammatory and infective conditions. Inflammation and infection boost this liver-produced acute phase reactant. ⁵ Albumin, on the other hand, is a liver-produced negative acute phase reactant that diminishes during inflammation. Albumin is also associated with disease severity and mortality. ⁶

CRP-to-albumin (CRP/alb) ratio was recently discovered as a new prognostic score associated with inflammation severity and mortality even though there is still no consensus on normal values of CRP/alb ratio. Some studies already tried to establish the relationship between CRP/alb ratio to AP severity and mortality and most of them yielded positive results. However, there is no meta-analysis that is currently available that summarizes all of these studies findings.

In this study, a systematic review and meta-analysis were conducted to investigate the prognostic value of CRP/alb ratio in AP.

Methods

This systematic review and meta-analysis conforms to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. We registered this review in PROSPERO (registration number: CRD42023427438).

Literature search

We performed a systematic literature search using PubMed, Science Direct, and Cochrane Library to find eligible journals from their commencement to January 31st, 2023. We employed keywords “pancreatitis” AND (“CRP albumin ratio” OR “C-reactive protein/albumin” OR “C-reactive protein albumin” OR “CRP/albumin” OR “CRP alb ratio” OR “CRP/alb”). Additionally, we examine the references of pertinent articles. Duplicate results were removed after the initial search.

Study selection

Three authors (IKM, CPS, DAS) independently performed study selection. A screening of study titles and abstracts was undertaken to exclude irrelevant literature. The inclusion and exclusion criteria for this review were applied to studies that passed the initial screening. The studies were included if they met all of the mentioned criteria: (1) observational studies reporting patients with acute pancreatitis, (2) reporting CRP/alb ratio on admission, (3) adult patients, (4) reporting the AP severity and/or patient’s mortality, (5) articles in English or Indonesian. Moreover, the studies were excluded if they meet one of the following criteria: (1) no full text available, (2) case reports, (3) conference papers, (4) review articles, (5) non research letters and (6) commentaries, (7) did not provide the necessary data for conducting meta-analysis.

Data extraction

Data of the included studies that were extracted are the first author’s name, year of publication, country, type of study, number of patients, age, CRP/alb ratio means or median value, and outcomes (severity or mortality).

The primary outcome studied in the present systematic review and meta-analysis is severity of AP. The secondary outcome was the mortality of AP patients. All authors utilized an electronic data collection form to acquire the necessary information from each article.

Risk of bias

The Newcastle–Ottawa scale (NOS) was adopted to assess the risk of bias in each study included. Three authors (IKM, CPS, DAS) independently conducted this process. The investigations were divided into three categories: low risk (6), moderate risk (4–5), and high risk (3).

Statistical analysis

Review Manager 5.4 and Stata 17 were used as the softwares for statistical analysis. We estimated the pooled mean difference (MD) with 95% confidence intervals (CI) using the mean difference (MD) and standard deviation (SD) from each study. We utilized a calculator by Luo et al. and Wan et al. to determine the mean if data were provided as median with Q1 and Q3 or range. ⁷ ^, ⁸ Heterogeneity was assessed using the I ² statistic, which reveals which percentage of the variation in observed impacts across studies is related to the variation in true effects, with values greater than 60% indicating significant heterogeneity. All P values were two-tailed, and <0.05 was regarded statistically significant. Forest plot was generated to give a visual suggestion of the amount of study heterogeneity and the estimated effect. The leave-one-out method (repeating the analysis after eliminating one study at a time) was used to conduct a sensitivity analysis.

Results Study selection and characteristics

The keywords search yielded a total of 21 publications. After eliminating the duplicates, we retrieved 18 publications. By screening the titles and abstracts, we excluded 7 studies, leaving us with 11 potential studies. Then, the full texts of the potential studies were obtained and reviewed to see if they were eligible for inclusion in the meta-analysis. Publications that did not offer all the necessary data for this meta-analysis and that did not fulfill all the inclusion criteria were excluded. Thereby, in the present study, a total of 6 studies were included. ⁹ ^– ¹⁴ PRISMA study flow diagram is described in Figure 1.

Figure 1. PRISMA flow diagram.

All 6 included studies were retrospective cohorts, with a total of 2244 patients. All studies were published in 2017–2022. Based on the study location, 4 studies were conducted in Turkey and 2 in China. There were 5 studies that evaluated CRP/alb relationship with AP severity. Meanwhile, the relationship between CRP/alb ratio with AP mortality were evaluated in 2 studies. Table 1 showed the characteristics of the included studies.

Table 1. Characteristics of the studies included in the meta-analysis.

Study	Country	Study design	Assessment of severity	Sample	Mean/median age	Non-severe/severe	Survivors/non-survivors	Cut-off severe	Cut-off mortality
Karabuga 2022	Turkey	retrospective observational study	BISAP score	female 253 (50.6%) male 247 (49.4%)	55.68 ± 18.30	mild 388 severe 112	survivor 473 death 23	>0.0015
Kiyak 2022	Turkey	retrospective observational study	Balthazar and Ranson score	female 173 (52.6%) male 156 (47.5%)	male 50.3 ± 15.7 female 54.3 ± 17.4	mild 238 severe 91		>5.34	Mortality (-) 3.3 ± 2.6 (+) 6.5 ± 1.2
Ugurlu 2022	Turkey	retrospective observational study	contrast-enhanced abdominal computed tomography (CECT) and Revised Atlanta Classification	582 female 344 (59.1%) male 238 (40.8%)	male 58.06 ± 17.34 female 57.9 ± 21.05	AEP 525 ANP 57	survivor 541 death 41	> 0.878
Yilmaz 2018	Turkey	retrospective observational study	Ranson score	264 female 159 (60.2%) male 105 (39.8%)	59.97 ± 17.47	moderate 204 severe 60	no mortality	>8.51
Zhao 2020	China	retrospective observational study		140 female 42 (30%) male 98 (70%)	49.88 ± 13.94		survivor 124 death 16		>7.69
Zhao 2023	China	retrospective observational study	severe AP defined as persistent single or multiple organ failure (>48 h)	284	59.50 (IQR 39.00–70.00)	non severe 249 severe 35	survivor 273 death 11	>5.03	>5.33

Quality assessment

Using the NOS to evaluate the risk of bias, five studies were found to be at low risk, while one study was at high risk. Table 2 showed the risk of bias assessment.

Table 2. NOS of the studies included in the meta-analysis.

Study	Selection				Comparability	Outcome
Study	Representativeness of the exposed cohort	Selection of the nonexposed cohort	Ascertainment of exposure	Demonstration that outcome of interest was not present at start of study	Comparability of Cohorts	Assessment of outcome	Was follow-up long enough for outcomes to occur	Adequacy of follow up of cohorts	SCORE	Evidence quality
Karabuga 2022	*	*	*		*	*	*	*	7	Low risk of bias
Kiyak 2022	*	*	*			*	*	*	6	Low risk of bias
Ugurlu 2022	*	*	*	*	*	*	*	*	8	Low risk of bias
Yilmaz 2018		*		*		*	*	*	5	Moderate risk of bias
Zhao 2020	*	*	*	*		*	*	*	7	Low risk of bias
Zhao 2023	*	*	*		*	*	*	*	7	Low risk of bias

CRP/alb ratio and AP severity

Five studies with a total of 1960 patients analyzed the relationship between CRP/alb ratio and AP severity. Severe AP patients had higher CRP/alb ratio than non-severe AP patients (pooled MD: 3.59; 95% CI: 2.51-4.68; p < 0.00001) ( Figure 2). In addition, a sensitivity analysis was performed with leave-one-out method due to severe heterogeneity (I ² = 89%). Leave-one-out analysis showed no significant change in results after excluding one study at a time ( Figure 3).

Figure 2. Forest plot of studies comparing CRP/alb ratio in severe vs non severe AP patients. Figure 3. Leave-one-out analysis of CRP/alb ratio comparison of severe and non severe AP patients. CRP/alb ratio and AP severity

We found only two studies evaluating AP mortality and CRP/alb ratio that fulfilled the inclusion criteria. Based on these studies, non-survivor patients had higher CRP/alb ratio than survivor patients (pooled MD: 2.12; 95% CI: 0.43-3.8; p < 0.01) ( Figure 4).

Figure 4. Forest plot of studies comparing CRP/alb ratio in survivor vs non survivor AP patients. Discussion

In patients with AP there is a local inflammation that can cause systemic effects. This systemic inflammation is prone to develop systemic organ dysfunction and later organ failure. ¹⁵ Severity of AP is classified based on the presence of these systemic complications and organ failure, with severe AP is defined as persistent organ failure. Meanwhile in mild AP there are no systemic complications or organ failure. ¹⁶

Because the severity of AP is determined by how much inflammation there is, markers of inflammation are thought to determine the prognosis of AP. CRP, as one of the most commonly used biomarkers, has been shown to correlate well with AP severity. The problem was CRP levels alone at admission showed poor predictive value, and the correlation only significant when assessed later at 48 hours from admission. The accepted number by international consensus for prediction of severe AP was CRP >150 mg/L within the first 48 hours. ¹⁷ Several studies discovered that both CRP and albumin can be beneficial in prognosis determination of various diseases. Combination of these two markers is expected to produce a more superior predictive value than using only one of them.

In this meta-analysis, we noted that the CRP/alb ratio is a promising prognostic score that can be used for the prediction of severity and mortality in AP patients. We analyzed 6 studies that fulfilled our inclusion criteria. Four studies from Turkey and 2 studies from China. Several included studies have different measurement units of CRP and albumin and some did not mention specifically what measurement units that were used. We tried to contact each corresponding author of the study in question to clarify this problem but none gave a response, thus we estimate the measurement units based on other relevant data from each study and make it all in the same measurement units.

We found that severe and non-survivor AP patients had higher CRP/alb ratio at admission than those with non severe and survivor AP patients. These findings were in line with results from other studies in recent years that showed the benefit of CRP/alb ratio as a prognostic marker in a variety of diseases. Because inflammation and carcinogenesis are linked, several systematic studies revealed the predictive practicality of CRP/alb ratio in different types of cancers. ¹⁸ ^, ¹⁹ Several studies tried to determine this association focusing on critically ill patients. Park et al. in their single center retrospective study found out that higher CRP/alb ratio was associated with increased mortality in ICU patients. ²⁰ Wang et al. discovered that critically ill acute kidney injury patients with greater CRP/alb ratios had higher in-hospital mortality and 2-year all-cause mortality. ²¹

A retrospective cohort by Oh et al. showed that a high CRP/alb ratio in intensive care unit-admitted patients is an independent risk factor for a 30-day mortality rate. ²² The results from this current meta-analysis reveal that CRP/Alb ratio may also serve as a reliable prognostic marker in patients with AP. AP is a disease that in severe form often leads to admission in the intensive care unit. This might explain the similar findings of this current study and previous study that focuses on critically ill patients.

Based on our knowledge, this is the first meta-analysis that evaluates CRP/alb ratio as a prognostic marker in AP patients. There is one systematic review by Tarar et al. that also assessed the prognostic value of CRP/alb ratio in AP patients, but that study just did the qualitative analysis based on 3 retrospective cohort studies and did not conduct meta-analysis. That study discovered an overall beneficial connection between the CRP/alb ratio at admission and the occurrence of severe AP as well as a longer hospital stay. ²³ These outcomes are consistent with the results of our study.

Nevertheless, our research has its own limitations. First, 6 studies that included in this meta-analysis only came from 2 countries, which are Turkey and China. We cannot explain this lack of variety in study location, but we can say that this lack of diversity has been a limitation in this current study. Second, the differences in the units of measurement that were used in each study lead to the possibility of inaccurate comparisons made in this study.

Conclusion

Our meta-analysis showed that high CRP/Alb ratio is associated with severe AP and mortality in patients with AP. Thus, CRP/alb ratio can be used as an early predictor of poor prognosis in patients with AP. However, due to the study’s limitations, large-scale trials involving patients of various ethnicities will be needed to verify the results we obtained.

Data availability Underlying data

No data are associated with this article.

Extended data

Zenodo: Prognostic role of C-reactive protein-to-albumin ratio in acute pancreatitis: a systematic review and meta-analysis (extended data), https://doi.org/10.5281/zenodo.8003368. ²⁴

This project contains the following extended data: -

Search strategy.docx

Reporting guidelines

Zenodo: PRISMA checklist for ‘Prognostic role of C-reactive protein-to-albumin ratio in acute pancreatitis: a systematic review and meta-analysis (extended data)’, https://doi.org/10.5281/zenodo.8003368. ²⁴

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

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10.5256/f1000research.148033.r182364

Reviewer response for version 1

Wibowo

Bogi Pratomo

1 Referee 1Faculty of Medicine, Brawijaya University, Malang, East Java, Indonesia

Competing interests: No competing interests were disclosed.

26 7 2023

2023

This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

recommendation

approve-with-reservations

REVIEW ARTICLE

This article addresses the prognostic value of CRP/albumin ratio in severity and mortality of acute pancreatitis. It addresses an important topic, especially the high CRP/albumin ratio as an early predictor of severity to conduct the doctors in charge immediately choose an appropriate therapeutic strategy. Despite the rather small study included in this meta-analysis, it should make an important contribution.

There are a number of issues with the inconsistency in the words chosen and the statistic analysis that need to be clarified. Below are more specific comments by section:

Abstract

The title stated prognostic role, in my opinion it should be prognostic value in conjunction with the statement of prognostic value of C-reactive protein-to-albumin ratio on the background of the abstract. The conclusion also stated the poor prognostic seems to be uncorrelated with the data reported in the article. It would be better using the term of severity or mortality in state of poor prognostic.

Introduction

More information about the epidemiology of acute pancreatitis would provide welcome context here. A bit more detail of incidence rate of acute pancreatitis in population would be helpful since you explicitly state acute pancreatitis is a common disorder on the background of the abstract.

Results

On the page 6 of 9, the double subtitles of CRP/alb ratio and AP severity should not be used. In my opinion, the subtitle should be CRP/alb ratio and AP severity and CRP/alb ratio and AP mortality. It is based on the primary and secondary outcome studied in this meta-analysis.

Table 2 – you indicate one study is moderate risk of bias with score 5, but in the text report of quality assessment is written high risk. This should be minimalized by cross-checking between the table shows and the text reported.

Figure 2 and 3 – the titles of forest plot are severe vs non severe patients, since you already make a case definition of non-severe as mild-moderate patients. It would be consistent if you use the title of severe vs mild-moderate patients.

Figure 4 – the heterogeneity of the forest plot is I ²=0% which means low heterogeneity, with p value 0.42 which means the heterogeneity test is not significant, so it would be better if you used the Fixed model rather than Random model analysis.

Discussion

Discussion of the CRP/alb ratio in cancer and critically ill patients is interesting, but it could be made much more succinct in keeping with the focus of acute pancreatitis patients on this article. More detail of the cut-off level of CRP/alb ratio here would be welcome.

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes

Is the statistical analysis and its interpretation appropriate?

Partly

Are sufficient details of the methods and analysis provided to allow replication by others?

Yes

Are the conclusions drawn adequately supported by the results presented in the review?

Yes

Reviewer Expertise:

Gastroenterologist

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Mariadi

I Ketut

Universitas Udayana, Denpasar, Bali, Indonesia

Competing interests: No competing interests were disclosed.

16 9 2023

Dear Dr. Bogi Pratomo Wibowo,

We sincerely appreciate the time and consideration you have provided in reviewing our manuscript.

Here we provide responses to your comments:

Abstract

Our response: Thank you for your suggestion. After the discussion by the authors, we agreed that “prognostic value” was more suitable for this study title, thus we changed the title with “Prognostic value of C-reactive protein-to-albumin ratio in acute pancreatitis: a systematic review and meta-analysis”.

For the conclusion in the abstract we tried to summarize our findings. Our findings showed that high CRP/alb ratio is associated with severe AP and mortality in patients with AP, thus we conclude that findings as poor prognostic. In the conclusion section in the full text we describe it in more detail than in the abstract.

Introduction

Our response: Thank you for your suggestion. We already added data of acute pancreatitis incidence rate in the introduction section as you suggested.

Results

Our response: Thank you for the correction. We already corrected the subtitles to the correct one: “CRP/alb ratio and AP severity” and “CRP/alb ratio and AP mortality”.

Our response: Thank you for the correction. We already corrected the mistakes. The score range of Newcastle-Ottawa Scale should be: low risk (7-9), moderate risk (4–6), and high risk (0-3). The one study that you mentioned has a score of 5, thus considered moderate risk of bias.

Our response: Thank you for your suggestion. We already changed the title of figure 2 and 3 with severe vs mild-moderate patients as you suggested.

Our response: Thank you for your suggestion. We already changed the statistical models that we used for the analysis between CRP/alb ratio with mortality as shown in figure 4 with the fixed-effect model as you suggested.

Discussion

Our response: Thank you for your suggestion. We already reduced the discussion about CRP/alb ratio in critically ill patients to keep the discussion focus on CRP/alb ratio in acute pancreatitis patients.

Thank you for your attention.

Sincerely,

I Ketut Mariadi

Division of Gastroenterology and Hepatology, Faculty of Medicine, Udayana University/Prof Dr. I.G.N.G. Ngoerah Hospital, Denpasar, Bali, Indonesia

10.5256/f1000research.148033.r182368

Reviewer response for version 1

Maulahela

Hasan

1 Referee https://orcid.org/0000-0002-0396-4433 1Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo National General Hospital, University of Indonesia, Depok, West Java, Indonesia

Competing interests: No competing interests were disclosed.

24 7 2023

2023

recommendation

approve-with-reservations

This is an important topic in the search for a simple prognostic marker for acute pancreatitis. The method chosen by the authors is strong (meta-analysis). Some additional information should be stated in the manuscript:

In the methods, who performed the literature search and what are their qualifications?

Any other attempts to acquire unpublished data?

From the studies we see that the severity criteria used are different for each study, how do the authors analyze this? Please explain more about it.

Explain more the possibility of more robust studies being excluded from the analysis because the authors cannot obtain the data (in the discussion).

Is there any risk of bias concerning the patient characteristics from the studies that were included in the analysis?

Are the rationale for, and objectives of, the Systematic Review clearly stated?

Yes

Is the statistical analysis and its interpretation appropriate?

Yes

Are sufficient details of the methods and analysis provided to allow replication by others?

Partly

Are the conclusions drawn adequately supported by the results presented in the review?

Yes

Reviewer Expertise:

Gastroenterology

Mariadi

I Ketut

Universitas Udayana, Denpasar, Bali, Indonesia

Competing interests: No competing interests were disclosed.

16 9 2023

Dear Dr. Hasan Maulahela,

We sincerely appreciate the time and consideration you have provided in reviewing our manuscript.

Here we provide responses to your comments:

1. In the methods, who performed the literature search and what are their qualifications?

Our response: The literature search and study selection performed by three authors (IKM, CPS, DAS) independently. IKM and DAS are internists in the Division of Gastroenterology and Hepatology, Faculty of Medicine, Udayana University/Prof Dr. I.G.N.G. Ngoerah Hospital, Denpasar, Bali, Indonesia. While CPS is a medical doctor at one of hospital in Jakarta

2. Any other attempts to acquire unpublished data?

Our response: We are not seeking any unpublished data since we could not determine the quality of the study. However, we try to obtain any incomplete data by tracking the supplementary information of the respective articles in our study.

3. From the studies we see that the severity criteria used are different for each study, how do the authors analyze this? Please explain more about it.

Our response: Thank you for your suggestion. We have added the discussion about different severity criteria that were used in each study in the “Discussion” section. Different severity criteria from each study were expected because each study was conducted in different countries and different centers. Each center usually has severity criteria of acute pancreatitis that is more often used than the other. But, we thought this difference did not significantly affect the results, because all the criteria were standardized criteria that are often used and in few studies already compared and showed no significant differences in their prognostic value.

4. Explain more the possibility of more robust studies being excluded from the analysis because the authors cannot obtain the data (in the discussion).

Our response: Thank you for your suggestion. We added the discussion about this in the discussion as you suggested. Some studies passed the screening process and fulfilled the inclusion criteria but eventually excluded because the statistical data provided by those studies were not clear. We tried to contact the corresponding author for those studies but none gave us response, thus the studies were excluded.

5. Is there any risk of bias concerning the patient characteristics from the studies that were included in the analysis?

Our response: Based on the risk of bias that we conducted using Newcastle-Ottawa Scale, most of the studies included were considered low risk of bias, with the exposed and non exposed individuals considered truly or somewhat representative of the target population.

Thank you for your attention.

Sincerely,

I Ketut Mariadi

Division of Gastroenterology and Hepatology, Faculty of Medicine, Udayana University/Prof Dr. I.G.N.G. Ngoerah Hospital, Denpasar, Bali, Indonesia