G Model YDLD-2832; No. of Pages 6
ARTICLE IN PRESS Digestive and Liver Disease xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
C-reactive protein as a prognostic indicator for rebleeding in patients with nonvariceal upper gastrointestinal bleeding Han Hee Lee, Jae Myung Park ∗ , Soon-Wook Lee, Seung Hun Kang, Chul-Hyun Lim, Yu Kyung Cho, Bo-In Lee, In Seok Lee, Sang Woo Kim, Myung-Gyu Choi Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 23 October 2014 Accepted 15 February 2015 Available online xxx Keywords: C-reactive protein Cohort studies Gastrointestinal haemorrhage Prognosis
a b s t r a c t Background: In patients with acute nonvariceal upper gastrointestinal bleeding, rebleeding after an initial treatment is observed in 10–20% and is associated with mortality. Aim: To investigate whether the initial serum C-reactive protein level could predict the risk of rebleeding in patients with acute nonvariceal upper gastrointestinal bleeding. Methods: This was a retrospective study using prospectively collected data for upper gastrointestinal bleeding. Initial clinical characteristics, endoscopic features, and C-reactive protein levels were compared between those with and without 30-day rebleeding. Results: A total of 453 patients were included (mean age, 62 years; male, 70.9%). The incidence of 30-day rebleeding was 15.9%. The mean serum C-reactive protein level was significantly higher in these patients than in those without rebleeding (P < 0.001). The area under the receiver operating characteristics curve with a cutoff value of 0.5 mg/dL was 0.689 (P < 0.001). High serum C-reactive protein level (odds ratio, 2.98; confidence interval, 1.65–5.40) was independently associated with the 30-day rebleeding risk after adjustment for the main confounding risk factors, including age, blood pressure, and initial haemoglobin level. Conclusions: The serum C-reactive protein was an independent risk factor for 30-day rebleeding in patients with acute nonvariceal upper gastrointestinal bleeding, indicating a possible role as a useful screening indicator for predicting the risk of rebleeding. © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Acute nonvariceal upper gastrointestinal bleeding (NVUGIB) is a common medical emergency with high morbidity [1]. Despite the advances in medications and therapeutic techniques, the rebleeding and mortality rates remain high in patients with NVUGIB [2]. Several prognostic scores have been developed to predict the outcomes for such patients with various predictors including age, comorbidities, initial blood pressure and heart rate, initial haemoglobin and urea levels, and endoscopic findings [3,4]. Because there has been no standard prognostic scoring system, many efforts have been made to develop accurate and simple clinical scores [5].
∗ Corresponding author at: Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea. Tel.: +82 2 2258 6022; fax: +82 2 2258 2089. E-mail address: [email protected] (J.M. Park).
C-reactive protein (CRP) is a nonspecific acute-phase reactant that is primarily synthesized by hepatocytes and regulated by cytokines such as interleukin-6 (IL-6) [6]. It acts as a key component of the innate immunity pathways and the concentration of CRP might increase rapidly more than 1000-fold above normal values as a response to inflammation, infection, or tissue damage [7,8]. CRP has been reported to be a prognostic indicator for various disorders, such as community-acquired pneumonia, ischaemic heart disease, and stroke [9–11]. Particularly in cardiovascular disease, the established guidelines emphasize the use of CRP for the assessment of cardiovascular risk in primary prevention [12]. Elevated levels of CRP and blood leucocyte counts were reported in highly active gastric inflammation in patients without other causes of acute inflammatory diseases [13], and with advanced gastric cancer [14]. Some studies have shown a correlation between low-grade inflammation as CRP and Helicobacter pylori infection [15,16]. The only study on the association of CRP and upper gastrointestinal (GI) bleeding reported a possible correlation between an increase of more than 100% in the CRP three months before endoscopy and GI bleeding [17], which suggested a possible
http://dx.doi.org/10.1016/j.dld.2015.02.008 1590-8658/© 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lee HH, et al. C-reactive protein as a prognostic indicator for rebleeding in patients with nonvariceal upper gastrointestinal bleeding. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.008
G Model YDLD-2832; No. of Pages 6
ARTICLE IN PRESS H.H. Lee et al. / Digestive and Liver Disease xxx (2015) xxx–xxx
2
relation between peptic ulcers and the upregulation of IL-6 and CRP. Highly active inflammation states of gastric lesions such as ulcers and erosions could affect the outcome of patients with GI bleeding. However, there are few studies on the association between CRP and NVUGIB. The hypothesis of this study was that the serum CRP level is a useful prognostic indicator for poor outcome among patients with acute NVUGIB. Our aims were to investigate the relationship between the 30-day rebleeding rate and initial levels of serum CRP in such patients, and to assess whether this measure might have any benefit as a prognostic indicator for rebleeding.
2. Methods 2.1. Patients This was a retrospective study using prospectively collected data from consecutive patients with upper GI bleeding at Seoul St. Mary’s Hospital, Korea between January 2010 and September 2013. All patients who had upper GI bleeding underwent endoscopy within 24 h of the event. Based on the endoscopic diagnosis, we screened for patients with acute NVUGIB. Patients who were younger than 18 years, hospitalized after cardiopulmonary arrest, or had variceal bleeding were excluded. Patient characteristics were recorded for the following variables: age, sex, alcohol consumption and smoking history, major comorbidities (malignancy, liver cirrhosis, or chronic renal failure), medication history, GI bleeding history, and initial vital signs. Initial laboratory tests included measures of haemoglobin, white blood cell count, serum blood urea nitrogen, and serum CRP. H. pylori infection was considered to be present if either the urease test or histology from the endoscopic biopsy samples was positive for the bacterium. The Institutional Review Board of our institution approved this study (KC13RISI0824).
2.2. CRP measurement and endoscopic data Serum CRP levels were measured with the Hitachi 7600 analyzer (Hitachi, Tokyo, Japan) using a CRP high-sensitivity turbidimetric immunoassay (Wako Pure Chemical Industries, Ltd., Osaka, Japan). The CRP assay reports results in mg/dL. Endoscopic data included the presence of blood in the stomach, cause of bleeding, Forrest classification (if a peptic ulcer was present), and detailed description of any method of endoscopic haemostasis [18]. The endoscopic haemostatic methods for stigmata of haemorrhage were injection of diluted epinephrine, application of hemoclips, thermal coaptive coagulation, band ligation, or a combination thereof. After the endoscopic haemostasis, adjuvant medical therapies, such as high-dose intravenous proton pump inhibitor (PPI), oral PPI, or histamine-2 receptor antagonist, were given according to the discretion of the doctor in charge.
2.4. Statistical analysis Descriptive statistics were used to characterize the demographic features of the study population. Continuous variables are expressed as the mean ± standard deviation (SD) or medians (interquartile range) and categorical variables are expressed as the number (percentage). Between-group comparisons were executed using unpaired t-tests, chi-squared tests, Fisher’s exact test or Wilcoxon rank testing, as appropriate. The area under the receiver operator characteristic (ROC) curve was used as a measure of diagnostic efficacy. The threshold value was determined as the highest sensitivity and specificity, and used as a cutoff value for dichotomization of CRP. The Wilcoxon signed-rank test was used for statistical analysis, and P values
ARTICLE IN PRESS Digestive and Liver Disease xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Digestive and Liver Disease journal homepage: www.elsevier.com/locate/dld
Alimentary Tract
C-reactive protein as a prognostic indicator for rebleeding in patients with nonvariceal upper gastrointestinal bleeding Han Hee Lee, Jae Myung Park ∗ , Soon-Wook Lee, Seung Hun Kang, Chul-Hyun Lim, Yu Kyung Cho, Bo-In Lee, In Seok Lee, Sang Woo Kim, Myung-Gyu Choi Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 23 October 2014 Accepted 15 February 2015 Available online xxx Keywords: C-reactive protein Cohort studies Gastrointestinal haemorrhage Prognosis
a b s t r a c t Background: In patients with acute nonvariceal upper gastrointestinal bleeding, rebleeding after an initial treatment is observed in 10–20% and is associated with mortality. Aim: To investigate whether the initial serum C-reactive protein level could predict the risk of rebleeding in patients with acute nonvariceal upper gastrointestinal bleeding. Methods: This was a retrospective study using prospectively collected data for upper gastrointestinal bleeding. Initial clinical characteristics, endoscopic features, and C-reactive protein levels were compared between those with and without 30-day rebleeding. Results: A total of 453 patients were included (mean age, 62 years; male, 70.9%). The incidence of 30-day rebleeding was 15.9%. The mean serum C-reactive protein level was significantly higher in these patients than in those without rebleeding (P < 0.001). The area under the receiver operating characteristics curve with a cutoff value of 0.5 mg/dL was 0.689 (P < 0.001). High serum C-reactive protein level (odds ratio, 2.98; confidence interval, 1.65–5.40) was independently associated with the 30-day rebleeding risk after adjustment for the main confounding risk factors, including age, blood pressure, and initial haemoglobin level. Conclusions: The serum C-reactive protein was an independent risk factor for 30-day rebleeding in patients with acute nonvariceal upper gastrointestinal bleeding, indicating a possible role as a useful screening indicator for predicting the risk of rebleeding. © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Acute nonvariceal upper gastrointestinal bleeding (NVUGIB) is a common medical emergency with high morbidity [1]. Despite the advances in medications and therapeutic techniques, the rebleeding and mortality rates remain high in patients with NVUGIB [2]. Several prognostic scores have been developed to predict the outcomes for such patients with various predictors including age, comorbidities, initial blood pressure and heart rate, initial haemoglobin and urea levels, and endoscopic findings [3,4]. Because there has been no standard prognostic scoring system, many efforts have been made to develop accurate and simple clinical scores [5].
∗ Corresponding author at: Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea. Tel.: +82 2 2258 6022; fax: +82 2 2258 2089. E-mail address: [email protected] (J.M. Park).
C-reactive protein (CRP) is a nonspecific acute-phase reactant that is primarily synthesized by hepatocytes and regulated by cytokines such as interleukin-6 (IL-6) [6]. It acts as a key component of the innate immunity pathways and the concentration of CRP might increase rapidly more than 1000-fold above normal values as a response to inflammation, infection, or tissue damage [7,8]. CRP has been reported to be a prognostic indicator for various disorders, such as community-acquired pneumonia, ischaemic heart disease, and stroke [9–11]. Particularly in cardiovascular disease, the established guidelines emphasize the use of CRP for the assessment of cardiovascular risk in primary prevention [12]. Elevated levels of CRP and blood leucocyte counts were reported in highly active gastric inflammation in patients without other causes of acute inflammatory diseases [13], and with advanced gastric cancer [14]. Some studies have shown a correlation between low-grade inflammation as CRP and Helicobacter pylori infection [15,16]. The only study on the association of CRP and upper gastrointestinal (GI) bleeding reported a possible correlation between an increase of more than 100% in the CRP three months before endoscopy and GI bleeding [17], which suggested a possible
http://dx.doi.org/10.1016/j.dld.2015.02.008 1590-8658/© 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Lee HH, et al. C-reactive protein as a prognostic indicator for rebleeding in patients with nonvariceal upper gastrointestinal bleeding. Dig Liver Dis (2015), http://dx.doi.org/10.1016/j.dld.2015.02.008
G Model YDLD-2832; No. of Pages 6
ARTICLE IN PRESS H.H. Lee et al. / Digestive and Liver Disease xxx (2015) xxx–xxx
2
relation between peptic ulcers and the upregulation of IL-6 and CRP. Highly active inflammation states of gastric lesions such as ulcers and erosions could affect the outcome of patients with GI bleeding. However, there are few studies on the association between CRP and NVUGIB. The hypothesis of this study was that the serum CRP level is a useful prognostic indicator for poor outcome among patients with acute NVUGIB. Our aims were to investigate the relationship between the 30-day rebleeding rate and initial levels of serum CRP in such patients, and to assess whether this measure might have any benefit as a prognostic indicator for rebleeding.
2. Methods 2.1. Patients This was a retrospective study using prospectively collected data from consecutive patients with upper GI bleeding at Seoul St. Mary’s Hospital, Korea between January 2010 and September 2013. All patients who had upper GI bleeding underwent endoscopy within 24 h of the event. Based on the endoscopic diagnosis, we screened for patients with acute NVUGIB. Patients who were younger than 18 years, hospitalized after cardiopulmonary arrest, or had variceal bleeding were excluded. Patient characteristics were recorded for the following variables: age, sex, alcohol consumption and smoking history, major comorbidities (malignancy, liver cirrhosis, or chronic renal failure), medication history, GI bleeding history, and initial vital signs. Initial laboratory tests included measures of haemoglobin, white blood cell count, serum blood urea nitrogen, and serum CRP. H. pylori infection was considered to be present if either the urease test or histology from the endoscopic biopsy samples was positive for the bacterium. The Institutional Review Board of our institution approved this study (KC13RISI0824).
2.2. CRP measurement and endoscopic data Serum CRP levels were measured with the Hitachi 7600 analyzer (Hitachi, Tokyo, Japan) using a CRP high-sensitivity turbidimetric immunoassay (Wako Pure Chemical Industries, Ltd., Osaka, Japan). The CRP assay reports results in mg/dL. Endoscopic data included the presence of blood in the stomach, cause of bleeding, Forrest classification (if a peptic ulcer was present), and detailed description of any method of endoscopic haemostasis [18]. The endoscopic haemostatic methods for stigmata of haemorrhage were injection of diluted epinephrine, application of hemoclips, thermal coaptive coagulation, band ligation, or a combination thereof. After the endoscopic haemostasis, adjuvant medical therapies, such as high-dose intravenous proton pump inhibitor (PPI), oral PPI, or histamine-2 receptor antagonist, were given according to the discretion of the doctor in charge.
2.4. Statistical analysis Descriptive statistics were used to characterize the demographic features of the study population. Continuous variables are expressed as the mean ± standard deviation (SD) or medians (interquartile range) and categorical variables are expressed as the number (percentage). Between-group comparisons were executed using unpaired t-tests, chi-squared tests, Fisher’s exact test or Wilcoxon rank testing, as appropriate. The area under the receiver operator characteristic (ROC) curve was used as a measure of diagnostic efficacy. The threshold value was determined as the highest sensitivity and specificity, and used as a cutoff value for dichotomization of CRP. The Wilcoxon signed-rank test was used for statistical analysis, and P values
