Journal of Gastrointestinal Surgery

https://doi.org/10.1007/s11605-019-04459-8

ORIGINAL ARTICLE

C-reactive Protein Is the Best Biomarker to Predict Advanced Acute

Cholecystitis and Conversion to Open Surgery. A Prospective Cohort
Study of 556 Cases
Mahdi Bouassida 1,2 & Slim Zribi 1,2 & Bassem Krimi 1,2 & Ghazi Laamiri 1,2 & Bassem Mroua 1,2 & Helmi Slama 1,2 &
Mohamed Mongi Mighri 1,2 & Mohamed M’saddak Azzouz 2,3 & Lamine Hamzaoui 2,3 & Hassen Touinsi 1,2

Received: 14 August 2019 / Accepted: 29 October 2019

# 2019 The Society for Surgery of the Alimentary Tract

Abstract
Background White blood cell levels (WBC) is the only biologic determinant criterion of the severity assessment of acute
cholecystitis (AC) in the revised Tokyo Guidelines 2018 (TG18). The aims of this study were to evaluate the discriminative
powers of common inflammatory markers (neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP)) compared with
WBC for the severity of AC, and the risk for conversion to open surgery and to determine their diagnostic cutoff levels.
Methods This was a prospective cohort study. Over 3 years, 556 patients underwent laparoscopic cholecystectomy for AC. Patients
were classified into two groups: 139 cases of advanced acute cholecystitis (AAC) (gangrenous cholecystitis, pericholecystic abscess,
hepatic abscess, biliary peritonitis, emphysematous cholecystitis), and 417 cases of non-advanced acute cholecystitis (NAAC).
Multiple logistic regression and receiver-operating characteristic curve analysis were employed to explore which variables (WBC,
CRP, and neutrophil-to-lymphocyte ratio (NLR)) were statistically significant in predicting AAC and conversion to open surgery.
Results On multivariable logistic regression analysis, male gender (OR = 0.4; p = 0.05), diabetes mellitus (OR = 7.8; p = 0.005),
3–4 ASA score (OR = 5.34; p = 0.037), body temperature (OR = 2.65; p = 0.014), and CRP (OR = 1.01; p = 0.0001) were
associated independently with AAC. The value of the area under the curve (AUC) of the CRP (0.75) was higher than that of WBC
(0.67) and NLR (0.62) for diagnosing AAC. CRP was the only predictive factor of conversion in multivariate analysis (OR =
1.008 [1.003–1.013]. Comparing areas under the receiver operating characteristic curves, it was the CRP that had the highest
discriminative power in terms of conversion.
Conclusion CRP is the best inflammatory marker predictive of AAC and of conversion to open surgery. We think that our results
would support a multicenter—international study to confirm the findings, and if supported, CRP should be considered as a
severity criterion of acute cholecystitis in the next revised version of the Guidelines of Tokyo.

Keywords Acute cholecystitis . Advanced acute cholecystitis . Conversion . CRP . White blood cell levels .
Neutrophil-to-lymphocyte ratio

Acute cholecystitis (AC), a common complication of gallblad- The accurate assessment of severity in patients with AC is
der stones, is one of the most common acute surgical diseases. clinically important to optimize the treatment and achieve a
better prognosis. The revised Tokyo Guidelines 2018 (TG18)
were proposed for the risk stratification of patients with AC, in
* Mahdi Bouassida order to plan a therapeutic strategy and to identify useful pre-
bouassidamahdi@yahoo.fr dictors for prognosis.1 According to these guidelines, diagnos-
tic criteria for acute cholecystitis include physical examination
1
Depatment of Surgery, Mohamed Tahar Maamouri Hospital, findings, laboratory results such as C-reactive protein (CRP)
Nabeul, Tunisia and white blood cell levels (WBC), as well as radiologic eval-
2
Faculty of Medicine of Tunis, Tunis El Manar University, uation. CRP level is only used as a diagnostic criterion of
Tunis, Tunisia acute cholecystitis, and it is not part of the determinant criteria
3
Depatment of Gastroenterology, Mohamed Tahar Maamouri of the severity assessment of the disease in the guideline. The
Hospital, Nabeul, Tunisia TG18 use WBC as one of the severity criteria.

The aims of this study were to evaluate the discriminative
powers of common inflammatory markers (neutrophil-to-lym-
phocyte ratio (NLR), and C-reactive protein (CRP)) compared
with WBC for the severity of AC, and the risk for conversion
to open surgery and to determine their diagnostic cutoff levels.
Methods
Patients
We conducted a prospective observational study in which we
included patients with acute calculous cholecystitis who re-
quired emergency laparoscopic cholecystectomy (LC).
The study was performed at Mohamed Tahar Maamouri
Hospital, from January 1, 2015, to December 31, 2017. This
study was carried out in compliance with the Declaration of
Helsinki and the current ethical guidelines and was approved
by the institutional research and ethics board of our hospital. A
diagnosis of acute cholecystitis (AC) at the emergency depart-
ment was made when all of the following criteria were satis-
fied: (1) one local sign of inflammation (Murphy’s sign or
right upper quadrant (RUQ) tenderness/pain), (2) one system-
ic sign of inflammation (fever, elevated C-reactive protein
(CRP) level/white blood cell (WBC) count), and (3) imaging
findings characteristic of AC on abdominal computed tomog-
raphy (CT) or ultrasound.1 The diagnosis of AC was con-
firmed according to the pathological findings of the excised
gallbladder after surgery. All patients provided written in-
formed consent before participation. Exclusion criteria includ-
ed any state of immunosuppression, previous ingestion of an-
tibiotics or anti-inflammatories, and pregnancy. We also ex-
cluded patients with any other acute biliopancreatic disorder
(cholangitis, pancreatitis, or common bile duct stones) and
patients operated by laparotomy. Finally 556 patients met
the inclusion criteria and were enrolled in the study.
Data Collection
Baseline variables included age, sex, body mass index (BMI)
kg/m2, comorbidities, and previous abdominal operations.
Clinical data included fever (> 38 °C), Murphy’s sign, tender
right upper quadrant (RUQ), muscle rigidity, and palpable
mass in the RUQ. Blood samples were obtained on admission
for the measurement of the levels of aspartate aminotransfer-
ase, alanine aminotransferase, total bilirubin, lactate dehydro-
genase, γ-glutamyl transpeptidase, alkaline phosphatase, cre-
atinine (Cr), C-reactive protein (CRP), as well as the white
blood cell count, neutrophil count, lymphocyte count, platelet
(Plt) count, international normalized ratio of prothrombin time,
and hemoglobin (Hb). The NLR was calculated by dividing
the neutrophil count by the lymphocyte count. Ultrasound
findings of gallstones, thickening of the gallbladder (GB) wall,
J Gastrointest Surg
GB dimensions, pericholecystic fluid collection, and intramu-
ral gas were assessed. Intraoperative information included op-
erative times, estimated blood loss, intraoperative complica-
tions (bleeding and bile duct injury), presence of severe inflam-
mation or dense adhesions, type of cholecystectomy required
(complete or subtotal), and need to conversion.
Treatment and Patient Follow-up
A treatment decision was made on the basis of patients’ gen-
eral condition and comorbidities. All patients received the
initial treatment including the administration of antibiotics.
All patients were treated with emergency LC by the same
surgical team specialized in advanced laparoscopic
procedures.
Subgroups Definitions
As WBC is a biologic factor taken place in grading the disease
according to the TG18,1 in order to avoid bias, we choose not
to use this classification in our study, thus the definition of the
severity grade was based on operative and histological find-
ings. We tried to respect, as much as possible the prospective
design of the study as the operating surgeon and the patholo-
gist were blinded to the biologic parameters.
Our patients were divided into two groups:
1- Advanced acute cholecystitis (AAC): 139 cases:
– Gangrenous AC: 120 cases
– Hepatic abscess: 5 cases
– Pericholecystic abscess: 10 cases
– Biliary peritonitis: 4 cases
2- Non-advanced acute cholecystitis: 417 cases.
Study Endpoints
The primary endpoint of this study was the comparative effi-
cacy of CRP level, WBC, and NLR in predicting AAC. The
secondary endpoint was the comparative efficacy of CRP lev-
el, WBC, and NLR in predicting conversion to open surgery.
Statistical Analysis
All statistical analyses were carried out using the IBM SPSS
Statistics software program, version 22.0 (SPSS Inc.,
Chicago, Illinois, USA). Continuous variables were presented
as the median and range. Categorical variables were presented
as numbers and percentages. Univariate analysis was per-
formed with the Student t test for continuous variables and
with the chi-square test for categorical variables. Logistic
J Gastrointest Surg
regression analysis was used to identify independent predic-
tive factors of advance AC and of conversion by calculation of
odds ratios and its 95% CI. A p ≤ 0.05 was considered statis-
tically significant. To evaluate the accuracy of predictive fac-
tors of AAC/conversion, the area under the curve (AUC) was
determined using receiver operating characteristic (ROC)
curves. AUC values were calculated to compare the ability
of each inflammatory marker to predict AAC/conversion.
The resulting statistical information was presented using for-
est plots. The optimal cutoff points of the factors were evalu-
ated using ROC curves and maximum Youden index. Values
of p < 0.05 were considered statistically significant.
Results
Characteristics of Study Population
The overall median age was 53 years, and women constituted
69.4% of the study group. 15.28% of patients had diabetes
mellitus, 26.25% had hypertension, and 4.8% had ischemic
cardiac disease. According to the American Society of
Anesthesiologists score (ASA score), 58.4% of patients were
ASA 1, 34.9% were ASA 2, 6.47% were ASA 3, and 0.18%
were ASA 4. The median duration of symptoms was 2.2 days.
11.69% of patients had a systemic inflammatory response
syndrome (SIRS) at admission.
Right upper quadrant (RUQ) pain was the most common
symptom, and RUQ muscle rigidity on examination was ob-
served in 33.81% of patients. 43.33% of patients were oper-
ated in the same day of admission, and 56.67% were operated
later at the latest 3 days after the admission.
Twenty-five percent of patients had advanced acute chole-
cystitis (AAC), and 75% had non-advanced acute cholecysti-
tis (NAAC). In the AAC group, the patients had longer oper-
ative time, higher rate of conversion to open surgery and over-
all postoperative morbidity rates, and longer hospital stays
compared with the NAAC group (Table 1).
Predictive Factors of AAC
The results of the univariate analysis to determine the predic-
tive factors of AAC are shown in Table 2. On univariable
logistic regression analysis, the predictive factors of AAC
were: male gender, diabetes mellitus, ischemic cardiac dis-
ease, 3–4 ASA score, body temperature, RUQ muscle rigidity
on examination, white blood cell count (WBC), neutrophil-to-
lymphocyte ratio (NLR), CRP, SIRS, and pericholecystic ex-
udate in ultrasonography. On multivariable logistic regression
analysis, male gender (OR = 0.4; p = 0.05), diabetes mellitus
(OR = 7.8; p = 0.005), 3–4 ASA score (OR = 5.34 ; p = 0.037),
body temperature (OR = 2.65; p = 0.014), and CRP (OR =
1.01; p = 0.0001) were associated independently with AAC.
Comparison for Assessing the Discriminative Ability
of Each Inflammation Biomarker to Predict AAC
ROC curves were generated for diagnosing AAC, and the
AUC values were
compared with assess the predictive ability of each
inflammation-based prognostic parameter (Fig. 1).
Cutoff value of CRP in diagnosing AAC was 60.5 mg/L.
Sensitivity at the cutoff point was 71%, specificity 71.4%, and
the AUC at the cutoff point was 0.75. WBC cutoff value in
diagnosing AAC was 11950 el/mm3. Sensitivity at the cutoff
point was 65%, specificity 64.5%, and the AUC at the cutoff
point 0.67. NLR cutoff value in diagnosing AAC was 3.87.
Sensitivity at the cutoff point was 62%, specificity 62.5%, and
the AUC at the cutoff point 0.62.
Predictive Factors of Conversion to Open Surgery
Conversion to open surgery occurred in 75 cases (13.48%).
Conversion was most frequently needed for local inflamma-
tion (60 cases). The site of inflammation that necessitated
conversion was the Calot’s triangle in 51 cases and the gall-
bladder in nine cases. Intraoperative bleeding that was diffi-
cult to control was the reason for the conversion in nine pa-
tients; the site of bleeding was the cystic artery in six cases and
oozing around the gallbladder in three cases .Conversion was
needed due to dense pericholecystic omental and bowel adhe-
sions in five cases. Bile duct injury occurred in one case im-
posing the conversion.
Univariate analysis showed that the risk factors for conver-
sion to open surgery included age, duration of symptoms,
CRP, and pericholecystic exudates in ultrasonography
(Table 3). Multivariate analysis with a multiple logistic regres-
sion model showed that CRP was the only significantly inde-
pendent predictive factor of conversion in patients with AC
(OR = 1.008; p = 0.03).
Comparison for Assessing the Discriminative Ability
of Each Inflammation Biomarker to Predict
Conversion to Open Surgery
The optimum cutoff for CRP to predict conversion to open
surgery using the ROC analysis was 76 mg/L. The sensitivity
and specificity at the cutoff point were 66.7 and 66.7%, re-
spectively. The AUC at the cutoff point was 0.71 (Fig. 2).
The optimum cutoff for WBC to predict conversion to open
surgery using the ROC analysis was 12,650 el/mm3. The sen-
sitivity and specificity at the cutoff point were 55.6 and
57.7%, respectively. The AUC at the cutoff point was 0.59.
The optimum cutoff for the NLR to predict conversion to
open surgery using the ROC analysis was 4.6. The sensitivity
and specificity at the cutoff point were 61 and 61.3%, respec-
tively. The AUC at the cutoff point was 0.61.
 J Gastrointest Surg

Table 1 Operative parameters

and outcomes of AAC and Total population AAC NAAC p
NAAC
Operative time (min) 91.36 (25-320) 113 (35-320) 84 (25-300) 0.003
Conversion 13.48% 28% 8.6% 0.0001
Overall complications 3.59% 6.4% 2.6% 0.035
Hospital stay (hours) 54 (7–570) 56.4 (7–570) 40 (7–386) 0.012

NAAC non-advanced acute cholecystitis; AAC advanced acute cholecystitis

Data are presented as median (interquartile range) or percentage

Discussion CRP is an acute-phase protein with a half-life of 19 h. It is

Early prediction of AAC is important, because, as we found in
this study, this condition is associated with higher rate of con-
versions to open surgery, higher rate of difficult laparoscopic
cholecystectomy and higher morbidity than NAAC. In the
present study, we found that CRP level was the most impor-
tant biomarker for detecting AAC: first because it was the only
biologic parameter correlated significantly with AAC in mul-
tivariate analysis, and second because it had a better discrim-
inative power in the diagnosis of AAC than WBC and NLR.
Finally, we showed in the current study, that CRP level was
the only predictive factor of conversion to open surgery.
In TG 18, CRP, a well-known acute phase reactant is in-
cluded in the laboratory findings for the diagnosis of acute
cholecystitis.1, 2 However, white blood cell count is the only
biologic factor taken place in grading the disease according to
the guidelines; the predictive value of CRP has not been de-
termined and accepted among prognostic factors yet.
synthesized and secreted by the liver in response to
interleukine-6 and other proinflammatory cytokines. CRP ac-
tivates the classical complement cascade and stimulates
phagocytosis.3 CRP shows increased levels in various inflam-
matory processes.
Several previous publications tried to study the correlation
between CRP level and the severity of AC4–8 and to compare
performance of CRP and WBC in the determination of sever-
ity of AC.9, 10 Sato et al.4 had shown that CRP/albumin ratio is
significantly elevated in patients with AC according to the
severity grade. However, the definition of the severity grade
differed between their study and the present study as the se-
verity grade of Sato et al. was based on the TG13, whereas
ours was based on the surgical and the histological findings.
Nikfarjam et al.5 found that gangrenous cholecystitis has
significantly higher CRP than non-gangrenous cholecystitis
(94 mg/L vs.17 mg/L), whereas in the study of Mok et al.,6
they found this to be 330 mg/L vs. 20 mg/L. The study by

Table 2 Predictive factors of AAC

AAC NAAC P univ P multiv OR 95% CI

Age (years) 58 (19–91) 51 (18–93) 0.18 - - -

Male gender 49% 24% 0.0001 0.05 0.4 [0.16–1]
Hypertension 29% 25% 0.31 - - -
Diabetes 20% 13% 0.035 0.005 7.8 [1.8–32]
Cardiac disease 9.3% 3.3% 0.004 Ns - -
ASA 3-4 10% 5% 0.017 0.037 5.34 [1.1–27]
Duration of symptoms (days) 2.8 (1–7) 1.2 (1–7) 0.28 - - -
Temperature °C 37.7 (37–39.2) 37.4 (37–37.9) 0.0001 0.014 2.65 [1.2–5.7]
Muscle rigidity 54% 27% 0.0001 Ns - -
WBC/mm3 15015 (12,500–39,800) 1095 (3400–29,600) 0.0001 Ns - -
NLR 5.04 (0.82–11.9) 3.82 (0.66–17.3) 0.011 Ns - -
CRP (mg/L) 126 (6–371) 56 (1–264) 0.015 0.0001 1.01 [1.004–1.016]
SIRS 28% 6% 0.0001 Ns - -
Thickening of the gallbladder wall (mm) 6.07 (2–14) 5.06 (1.8–15) 0.16 - - -
Pericholecystic exudate 10% 3.8% 0.005 Ns - -

NAAC non-advanced acute cholecystitis; AAC advanced acute cholecystitis; WBC white blood cell; NLR neutrophil-to-lymphocyte ratio; SIRS systemic
inflammatory response syndrome; P univ p univariate; P multiv p multivariate; Ns not significant
Data are presented as median (interquartile range) or percentage
J Gastrointest Surg

Fig. 1 Forest plot of

inflammatory markers for
predicting advanced acute
cholecystitis

Juvonen et al.7 showed that large increases in CRP were as-
sociated with both infected bile and gangrene of the gallblad-
der. They also found that an elevated CRP value of more than
200 mg/dl had a 50% positive predictive value and a 100%
negative predictive value for predicting gangrenous cholecys-
titis with 100% sensitivity and 87.9% specificity. Gurbulak
et al.8 showed that the serum CRP level at admission was a
predictor in classifying different severity grades of AC defined
by the TG 13 severity grade.
In the current study, we found that CRP had a better dis-
criminative power in the diagnosis of AAC than WBC. These
findings extend those of Beliaev et al.,9, 10 confirming that

Table 3 Predictive factors of conversion to open surgery

Conversion No conversion P univ P multiv OR 95% CI

Age (years) 58 (19–89) 52.74 (18–93) 0.011 Ns - -

Male gender 38.66% 29.31% 0.1 - - -
Hypertension 32% 25.36% 0.22 - - -
Diabetes 17.33% 14.96% 0.59 - - -
Cardiac disease 5.33% 4.78% 0.77 - - -
ASA 3-4 8% 6.23% 0.56 - - -
Duration of symptoms (days) 2.8 (1–7) 2.1 (1–7) 0.0001 Ns - -
Temperature °C 37.6 (37–39.2) 37.47 (37–37.9) 0.067 - - -
Muscle rigidity 42.66% 32.43% 0.081 - - -
WBC/mm3 12372 (3400–31,000) 11,925 (4400–39,800) 0.47 - - -
NLR 4.17 (0.78–12.44) 4.12 (0.66–17.3) 0.85 - - -
CRP (mg/L) 142 (6–371) 70 (9–311) 0.001 0.03 1.008 [1.003–1.013]
SIRS 14.66% 11.22% 0.38 - - -
Thickening of the gallbladder wall (mm) 5.72 (2–12) 5.26 (1.8–15) 0.064 - - -
Pericholecystic exudate 10.66% 4.57% 0.03 Ns - -

WBC white blood cell; NLR neutrophil-to-lymphocyte ratio; SIRS systemic inflammatory response syndrome; P univ p univariate; P multiv p multivar-
iate; Ns not significant
Data are presented as median (interquartile range) or percentage

Fig. 2 Forest plot of
inflammatory markers for
predicting conversion to open
surgery
CRP value was a useful marker for stratifying the severity of
AC defined pathologically. They also found that the discrim-
inative power of the serum CRP value was superior to that of
the WBC, but unlike our study, it was similar to that of NLR in
discriminative ability.10
Early laparoscopic cholecystectomy became the gold stan-
dard in the management of AC,11 but this strategy is not al-
ways possible in a healthcare system with constrained re-
sources, which cannot provide emergency cholecystectomy
to all patients who present with acute cholecystitis. In our
department, patients with higher CRP are likely to benefit
from emergency cholecystectomy even in the same day of
admission during the afterhours period.
Previous studies focused on the rate of conversion from
laparoscopic to open surgery, ranging from 2 to 10%, and
the risk factors associated with conversion.12 This would al-
low surgeons to better inform patients about the risk of con-
version from laparoscopic to open cholecystectomy and to
implement specific strategies to decrease the rates of conver-
sion (selection of surgeons, decrease of preoperative time,
subtotal cholecystectomy, antegrade, or fundus first
techniques).13
Molk et al. ,14 described cutoff points of CRP for predicting
conversion. They found that patients with CRP < 220 mg/L
(3.2%) had significantly less chance of conversion than those
with CRP > 220 mg/L (61.9%). Wevers et al.15 showed that an
elevated CRP value with a cutoff value of 165 mg/L was an
independent predictor for conversion to open cholecystectomy.
J Gastrointest Surg
Diaz-Flores et al.,16 found that preoperative CRP with values >
110 mg/L was associated with the highest odds (OR = 17.9) of
presenting difficult laparoscopic cholecystectomy.
When reviewing the literature, we found that the majority
of publications12, 17–19 aiming to find predictive factors of
conversion based their results on comparative analysis, lack-
ing of true predictive model analysis with ROC curve and
AUC analysis, as well as sensitivity and specificity.16 In our
study, we tried to explore the value of CRP in predicting
conversion using both methods, and we found, first, that
CRP was the only significantly independent predictive factor
of conversion in patients with AC (we should note that al-
though predictive the odds of having to convert are still rela-
tively low), and second that, compared with WBC and NLR,
CRP had a better discriminative power in predicting conver-
sion to open surgery.
Limitations
In the current work, we tried to respect, as much as possible
the prospective design of the study as the operating surgeon,
and the pathologist were blinded to the biologic parameters.
This study has several limitations. First as it was conducted in
the surgical department of a single hospital, the sample size
was small. In addition, patient exclusion could have resulted
in selection bias. Second, we did not analyze the usefulness of
CRP, WBC, and NLR for evaluating treatment response by
assessing changes in their values after definitive treatment.
J Gastrointest Surg
In conclusion, CRP was the only inflammatory marker pre-
dictive of advanced AC and of conversion to open surgery.
CRP had the highest discriminative power in diagnosing ad-
vanced AC with a good sensitivity (71%) and specificity
(71%). It had also the highest discriminative power in
predicting conversion.
We think that our results would support a multicenter—
international study to confirm the findings, and if supported,
CRP should be considered as a severity criterion of acute
cholecystitis in the next revised version of the Guidelines of
Tokyo.
Authors’ Contribution Mahdi Bouassida, Slim Zribi, Bassem Krimi, and
Ghazi Laamiri did the conception and the design of the work
Bassem Mroua, Helmi Slama, Mohamed Mongi Mighri, and Lamine
Hamzaoui did the acquisition and the analysis of the data
Hassen Touinsi and Mohamed M’saddak Azzouz revised the work
critically
Compliance with Ethical Standards
Conflict of Interest Drs Mahdi Bouassida, Slim Zribi, Bassem Krimi,
Ghazi Laamiri, Bassem Mroua, Helmi Slama, Mohamed Mongi Mighri,
Mohamed M’saddak Azzouz, Lamine Hamzaoui and Hassen Touinsi
have no conflicts of interest or financial ties to disclose.
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