Background
Acute cholecystitis accounts for most of the hospital admissions related to gastrointestinal diseases[
1]. In approximately 90% of patients, inflammation develops due to obstruction of the cystic duct by one or more gallstones[
2]. Delayed management can lead to increased morbidity, due to progression to severe cholecystitis, such as gangrenous change, abscess formation, and gallbladder perforation. The prevalence of severe cholecystitis has been reported to be 22–30% in surgical series[
3,
4]. Unfortunately, patients with severe cholecystitis are often challenging to accurately diagnose, both clinically and radiologically, since the clinical manifestations are unpredictable, and imaging studies are often equivocal[
5]. However, marked contrasts in the morbidity and mortality rates have been observed beween patients with simple cholecystitis and severe cholecystitis[
3,
6]. Therefore, prompt detection and proper management of patients at risk of severe cholecystitis are essential in preventing associated complications.
To predict the prognosis of inflammatory diseases and some malignancies, several inflammation-based scores have been suggested, including the Modified Glasgow Prognostic Score, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio, and prognostic Nutritional Index[
7,
8]. Of these, the NLR has received great interest, since it is simple to calculate, and involves no additional cost, as it uses results from a standard complete blood count test. The NLR is derived from the counts of circulating neutrophils and lymphocytes, both of which are major leukocyte subpopulations. The inflammation-triggered release of arachidonic acid metabolites and platelet-activating factors results in neutrophilia, and cortisol-induced stress results in relative lymphopenia, and thus, the NLR accurately represents the underlying inflammatory process[
9]. Increasing evidence supports the utility of the NLR in predicting the prognosis of inflammatory and malignant diseases, although the application of the NLR to inflammatory gallbladder disease has not been reported. In the present study, we aimed to evaluate the utility of the NLR as a prognostic indicator in patients with cholecystitis, and to identify a relevant NLR value that discriminates between simple and severe cholecystitis.
Methods
Study design and data collection
We retrospectively reviewed prospectively collected data from patients who underwent cholecystectomies in Daejeon St. Mary’s Hospital, the Catholic University of Korea, between March 2007 and February 2014. Furthermore, we verified the current data, and obtained additional data, by including the radiology and pathology reports as a part of this study. This study was approved by the ethics committee, Daejeon St. Mary’s hospital, College of Medicine, the Catholic University of Korea (IRB code: DC13RISI0087).
During the study period, 1,023 cholecystectomies were performed either by the open or laparoscopic approach. To clearly identify gallbladder inflammation, we only selected 993 patients in whom the pathology reports indicated the presence of cholecystitis. Of these, we first excluded the patients (n =197) who initially presented with no specific symptom for cholecystitis. We then excluded patients (n =164) whose time-to-incision, the time interval between arrival to the hospital and the performance of surgical incision, was 120 h or longer. Finally, a toal of 632 patients were selected for inclusion in this study. Each patient’s NLR was calculated at admission as the absolute neutrophil count divided by the absolute lymphocyte count, using data from their standard complete blood count test.
We conducted receiver operating characteristic (ROC) curve analyses to determine the cut-off value for preoperative NLR that could discriminate between simple and severe cholecystitis. The most prominent point on the ROC curve was chosen as the cut-off value for the NLR. We then divided the patient population into two groups, according to the cut-off value of NLR, and attempted to detect differences in the clinical variables between these two groups. Thereafter, we performed univariate and multivariate analyses to investigate the effect of the NLR on the length of hospital stay (LOS).
Terminology and definitions
Cholecystitis was defined by a histological finding of an inflammatory infiltrate on examination of the gallbladder wall. Severe cholecystitis was defined as a cholecystitis complicated by secondary changes, including hemorrhage, gangrene, emphysema, or perforation, and/or when the pathological examination indicated xanthogranulomatous cholecystitis; the representative forms of severe cholecystitis were gangrenous cholecystitis and gallbladder perforation. All other pathological findings were categorized as simple cholecystitis. Conversion was defined as the completion of any part of a procedure using an open technique except for minimal wound extension (≤10 mm) for specimen delivery. In addition, the incidence of an addition of ports during surgery was also counted. Operation time referred to the time interval between the initial skin incision and completion of wound closure, as documented by an anesthesiologist. With regard to intraoperative complications, bleeding referred to a loss of more than 200 mL during the operative procedure and gallbladder perforation referred to gross intraperitoneal bile contamination requiring irrigation. For postoperative complications, intra-abdominal hemorrhage referred to bleeding requiring transfusion, radiological, or surgical intervention; bile leak referred to persistent bile drainage from the drain site up to the 7th postoperative day or leakage requiring intervention; and voiding difficulty referred to the ongoing requirement for urinary catheterization up to the 7th postoperative day.
Statistical analysis
Data were described as means ± standard deviations, or as medians and ranges. Continuous variables were compared using the independent t-test, while categorical variables were compared using the chi-squared test. Multiple regression analyses were performed using a proportional hazards model to identify factors independently associated with the LOS greater than the 80th percentile after cholecystectomy, and to estimate corresponding odds ratio (OR) in 95% confidence intervals (CI). Statistical analysis was performed using SPSS version 15.0 (SPSS Inc., Chicago, IL). Statistical significance was accepted for P-values less than 0.05.
Discussion
Since severe cholecystitis is associated with more adverse clinical features than simple cholecystitis, prompt detection of the severe cholecystitis and surgical intervention before its further advancement is essential to avoid complications related to advanced histology. Patients with severe cholecystitis are at an increased risk of damage to the main biliary ducts, ligation of aberrant hepatic ducts, and injury to the right hepatic artery during surgery[
10]. Thus far, the detection of severe cholecystitis has typically relied on imaging studies, such as abdominal ultrasound and computerized tomography (CT) scanning. However, these studies occasionally fail to detect severe cholecystitis[
2,
5]. In the present study, we demonstrated that a preoperative NLR of 3.0 has the potential to differentiate between simple and severe cholecystitis. Therefore, the NLR calculation could be used to determine surgical priority by improving diagnostic accuracy when the CT findings are ambiguous, and by predicting a patient’s risk of progressing from simple to severe cholecystitis.
Patients with advanced inflammatory or malignant diseases usually present with elevated NLR as a manifestation of the systemic inflammatory response. Many investigators have attempted to identify the association between the NLR and its underlying molecular basis, and have found that there is an elevation in the levels of pro-inflammatory cytokines (e.g., IL-1ra, IL-6, IL-7, IL-8, IL-12) in the plasma of patients with elevated NLR[
11‐
13]. These inflammatory cytokines are expected to perpetuate a tissue microenvironment favoring aggressive inflammation or tumoral behavior. Furthermore, high peritumoral infiltration of macrophages was observed in cancer patients with elevated NLR[
12]. Therefore, elevated NLR appears to be an accurate indicator of up-regulation of the innate immune response.
The representative forms of severe cholecystitis are gangrenous cholecystitis and gallbladder perforation. Gangrenous cholecystitis occurs in up to 30% of patients with cholecystitis[
5], wherein inflammation causes interruption of blood flow to the gallbladder, resulting in gangrenous change. The mortality rate was reported to be up to 22%, and it is directly related to other severe complications, such as gallbladder perforation, abscess formation, and peritonitis[
14]. Gallbladder perforation is the eventual result of severe cholecystitis, where inflammation can either be localized or spread throughout the whole abdominal cavity via the perforated gallbladder[
15]. In both forms, inflammation is expected to result in elevated NLR, which validates our results.
This study shows the usefulness of preoperative NLR in predicting prognosis and therefore, in determining operative priority in patients with cholecystitis. Patients with acute severe cholecystitis have higher incidences of postoperative complications and a prolonged LOS[
16‐
19]. In this study, high NLR was found to be a predictor of severe cholecystitis as well as an independent risk factor for prolonged LOS. Early cholecystectomy was shown to decrease LOS in patients with acute severe cholecystitis[
20]. Therefore, prioritizing patients with high NLR for operation would reduce postoperative morbidity and LOS. Similarly, operation time was longer in the high NLR group than in the low NLR group. However, the incidences of open conversion or the addition of one or more port(s) were similar in the two groups.
To our knowledge, this study is the first to investigate the relationship between the NLR and cholecystitis. According to the disease entities or their severity, a range of NLR cut-off values have been proposed, usually from 3 to 8[
21]. Of these, a threshold of >5.0 has been most frequently proposed[
22‐
26], while recent reports have recommended a value of 3.0[
27‐
31]. We determined the cut-off value of severe cholecystitis as 3.0 based on our ROC curve analysis; the NLR value of 3.0 had an acceptable reliability in the analysis (70.5% sensitivity and a specificity of 70.0%). Therefore, we believe that a NLR cut-off value of 3.0 is suitable, and consistent with previous studies[
27‐
31]. However, further study is needed to validate our cut-off value, and to more precisely identify an optimal NLR with the greatest prognostic power in cholecystitis.
The limitations of this study are those common to all database research. Since it involved a retrospective review of prospectively collective data, the results should be confirmed by prospective trials. Moreover, when we divided our patient population according to the NLR cut-off value, patient distribution was not well-balanced; our higher NLR patients included more patients with older age and men. Therefore, age and sex may act as confounding factors, which may affect the conclusion that an NLR of 3.0 is independently related with the severity of cholecystitis. In addition, the incidence of acalculous cholecystitis herein was 19.1% which did not fall within the general range of 2% to 15% as noted by others[
32,
33]. Acute acalculous cholecystitis has been generally shown poor prognosis than acute calculous cholecystitis; the median NLRs of calculous cholecystitis and acalculous cholecystitis were 2.67 and 2.18, respectively (P =0.004). Therefore, in understanding our results, the differences in the composition of patient population should be taken into consideration.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SJK designed the study, and finally approved the version to be published, SCL and JWP equally contributed to acquiring and analyzing data, and SKL wrote the paper. All authors read and approved the final manuscript.