Abstract
Background:
Gallstones are a well-known risk factor for acute cholecystitis. However, their role as a risk factor for gallbladder perforation (GBP) remains unclear. Therefore, this study aimed to determine the effect of gallstones on the development of GBP.
Materials and methods:
This large-scale retrospective cohort study enroled consecutive patients who underwent cholecystectomy for acute cholecystitis. The primary endpoint was the role of gallstones as a risk factor for developing GBP. Secondary endpoints included the clinical characteristics of GBP, other risk factors for GBP, differences in clinical outcomes between patients with acalculous cholecystitis (AC) and calculous cholecystitis (CC), and the influence of cholecystectomy timing.
Results:
A total of 4497 patients were included in this study. The incidence of GBP was significantly higher in the AC group compared to the CC group (5.6% vs. 1.0%, P<0.001). However, there were no differences in ICU admission and hospital stay durations. The incidence of overall complications was significantly higher in the AC group than in the CC group (2.2% vs. 1.0%, P<0.001). Patients with AC had a higher risk of developing GBP than those with CC (odds ratio, 5.00; 95% CI, 2.94–8.33). In addition, older age (≥60 years), male sex, comorbidities, poor performance status, and concomitant acute cholangitis were associated with the development of GBP. Furthermore, the incidence of GBP was significantly higher in the delayed cholecystectomy group than in the early cholecystectomy group (2.0% vs. 0.9%, P<0.001).
Conclusions:
AC is a significant risk factor for GBP. Furthermore, early cholecystectomy can significantly reduce GBP-related morbidity and mortality.
Keywords: acalculous cholecystitis, calculous cholecystitis, cholecystectomy, gallbladder perforation, risk factor
Introduction
Highlights
Acalculous cholecystitis is a significant risk factor for gallbladder perforation.
Early cholecystectomy can significantly reduce gallbladder perforation-related morbidity and mortality.
The incidence of gallbladder perforation is relatively low; however, its implications are severe, warranting a high degree of suspicion, especially in high-risk patients such as those with acalculous cholecystitis.
In today’s advanced medical world, with technical innovations in laparoscopic surgeries and improvements in imaging methods, gallbladder (GB) perforation (GBP) remains a life-threatening complication of acute cholecystitis, even though its occurrence has decreased1–3. Current research has reported the incidence of GBP to be 2–11% among patients with acute cholecystitis4. This variation can be associated with the differences in study groups, varying levels of disease severity across the groups, and disparities in healthcare access and quality5,6.
To effectively prevent GBP, it is crucial to understand its associated risk factors. Notably, several factors have been identified to increase the risk of GBP, including delay in diagnosis, older age (>60 years), male sex, presence of comorbidities, and having symptoms for greater than 72 h before seeking medical attention2,7. Gallstones can obstruct the cystic duct or neck of the GB, leading to inflammation known as acute calculous cholecystitis (CC). The extent and duration of this obstruction determine the speed at which acute cholecystitis advances and the intensity of the GB’s inflammatory response8. There are three distinct stages (initial, subsequent, and final) in the development of acute cholecystitis after cystic duct blockage9. The initial stage involves inflammation, characterized by the congestion and swelling of the GB wall. The subsequent stage is characterized by bleeding and tissue necrosis of the GB wall, potentially leading to perforation at the area of gangrenous tissue, resulting in biliary peritonitis2. The final stage, known as the chronic or purulent phase, is characterized by the influx of white blood cells (WBCs), dead tissue, and pus formation. After the acute stage, the pus inside is gradually replaced by healing tissue, leading to subacute cholecystitis and, subsequently, chronic cholecystitis.
In contrast, the aetiology of acute acalculous cholecystitis (AC) is more complex and predominantly attributable to bile stasis or ischaemic events affecting the GB wall. Endothelial damage can provoke microvascular occlusion within the GB wall, resulting in ischaemia, particularly under hypoperfusion. This situation is especially common in severely ill patients who have undergone extended fasting or have ileus10,11. Notably, acute AC can advance to more severe pathologies, including gangrene, GB empyema, and spontaneous perforation, affecting ~50% of the patient population9.
It is important to study the relationship between GBP and gallstones, especially because gallstones are a leading cause of acute cholecystitis that can progress to GBP. However, the exact role of gallstones as a direct risk factor for GBP remains unclear because concrete evidence is still lacking. Therefore, this study aimed to evaluate the relationship between gallstones and GBP, the clinical outcomes of patients with GBP, and other risk factors for GBP using 10-year data from a single institution.
Materials and methods
Study population
Patient records of individuals who underwent cholecystectomy at our Hospital between November 2012 and June 2022 were retrospectively examined. Patients with acute cholecystitis according to the Tokyo Guidelines 2018 diagnostic criteria1, which encompassed local signs of inflammation (such as Murphy’s sign or right upper quadrant pain), systemic signs of inflammation (such as fever, elevated C-reactive protein level, or elevated WBC count), and characteristic imaging findings (such as GB wall thickening or pericholecystic fluid), were included in the study. A suspected diagnosis required one local and one systemic sign, while a definite diagnosis required a local sign, a systemic sign, and imaging evidence. The exclusion criteria were: (1) the presence of symptomatic gallstones without acute inflammation; (2) diagnosis of chronic rather than acute cholecystitis; and (3) detection of GB polyps or other neoplastic conditions lacking acute inflammatory indicators. Data on patient demographics including the Charlson Comorbidity Index (CCI)12, procedure specifics, and clinical outcomes, particularly the incidence of GBP and the presence of gallstones, were analyzed. This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the Ethics Committee at our Hospital (IRB no. 2022-04-008). Due to the study’s retrospective design, the requirement for informed consent was waived. In addition, this study has been reported in accordance with the STROCSS criteria13 for observational studies in surgery, Supplemental Digital Content 1, http://links.lww.com/JS9/B541. The corresponding checklist has been duly completed and can be made available upon request.
Outcomes and definitions
This study primarily aimed to assess the role of gallstones as a risk factor for developing GBP. The secondary objectives included the evaluation of other risk factors for developing GBP, characterization of GBP clinical features, and comparative analysis of clinical outcomes between patients with AC and CC.
Tokyo Guidelines 20181 have also classified the severity of acute cholecystitis into three grades: Grade I (mild), characterized by localized GB inflammation in healthy individuals; Grade II (moderate), characterized by systemic or intensified local symptoms such as tender mass or elevated WBC count; and Grade III (severe), characterized by associated organ dysfunction such as cardiovascular or respiratory complication1. GBP was confirmed based on pathologic reports of surgical specimens. Furthermore, Niemeier, in 1934, classified GBP into three types based on pathogenesis: Type I (acute perforation), defined as a free perforation into the peritoneal cavity, causing generalized peritonitis; Type II (subacute perforation), defined as a sub-serosal perforation leading to abscess formation usually adjacent to the GB; and Type III (chronic perforation), defined as a cholecysto-enteric fistula formation with or without a gallstone ileus (Fig. 1); this classification was used in the present study. Figure 2 provides a typical illustration for each variation of GBP. Gangrenous cholecystitis was also confirmed based on only pathologic reports of surgical specimens. The presence of gallstones was confirmed using various imaging techniques, including abdominal ultrasonography, computed tomography (CT), magnetic resonance imaging, and endoscopic ultrasonography, or directly during cholecystectomy. In addition, a postoperative pathological review was conducted after cholecystectomy to validate the presence of gallstones.
Figure 1.
Abdominal computed tomography scan and pathologic findings of gallbladder perforation. A case of severe gallbladder perforation in which gallstones were present or not. (A–D) Type I, acute free perforation of the gallbladder into the peritoneal cavity without protective adhesions. (E–H) Type II, subacute perforation surrounded by a pericholecystic abscess walled off by adhesions. (I–L) Type III, chronic perforation with fistulous communication between the gallbladder and viscus.
Figure 2.
Typical illustration for each variation of gallbladder perforation. (A) Type I, acute spontaneous rupture of the gallbladder into the abdominal cavity without shielding adhesions. (B) Type II, subacute rupture encompassed by a localized abscess around the gallbladder, enclosed by adhesions. (C) Type III, chronic rupture featuring a fistulous connection between the gallbladder and another organ.
Statistical analyses
In this study, continuous variables were presented as means and standard deviations (SD) or medians and interquartile ranges (IQR), depending on their distribution. Categorical variables were presented as frequencies and proportions. Student’s t-test was used to compare continuous variables, whereas the χ2 test was selected as the appropriate statistical method for categorical variables. Univariate and multivariate analyses were used to identify the risk factors associated with GBP. Multivariate analysis was further enhanced using logistic regression analysis. Variables with a P value of less than 0.2 in the univariate analysis were subsequently included as covariates in the multivariate analysis. Statistical significance was set at P less than 0.05 (two-sided). Statistical analyses were performed using the R software package (version 4.0.2) from the R Foundation for Statistical Computing (Vienna, Austria).
Results
Study population and baseline characteristics
A cohort of 5027 patients who underwent cholecystectomy was initially considered for this study, as shown in Fig. 3. Of this cohort, 530 patients were excluded based on the following criteria: presence of only symptomatic GB stones devoid of acute inflammation (n=419), chronic cholecystitis without acute inflammation (n=52), GB polyps or other neoplastic lesions without concurrent acute inflammation (n=59). Consequently, 4497 patients were included in the final analysis. Gallstone status was determined through radiological, surgical, and pathological evaluations. After assessment, patients were categorized into two groups: the ‘AC’ group, comprising patients without gallstones (n=539), and the ‘CC’ group, comprising patients with gallstones (n=3958).
Figure 3.
Study flow diagram. GB, gallbladder.
Patients’ baseline characteristics are presented in Table 1. The mean age was higher in the AC group than in the CC group (53.6±18.1 vs. 49.2±15.4 years, P<0.001). The AC group also had a significantly higher proportion of males (51.9%) than the CC group (51.9% vs. 47.3%; P=0.049). Regarding comorbidities, the CCI was significantly elevated in the AC group than in the CC group (0.4±0.8 vs. 0.3±0.7 P=0.004). The time interval from the onset of symptoms to hospital admission was significantly shorter in the AC group than in the CC group (3.3±3.9 vs. 4.0±4.5 days, P<0.001). Conversely, the duration from hospital admission to surgical intervention was longer in the AC group than in the CC group (3.7±5.8 vs. 2.7±3.0 years, P<0.001). The prevalence of acute cholangitis was higher in the AC group than in the CC group (31.5% vs. 26.0%, P=0.007). However, there was no significant difference in the prevalence of endoscopic retrograde cholangiopancreatography between the two groups. Furthermore, the prevalence of percutaneous transhepatic GB drainage (PTGBD) procedure was significantly higher in the AC group than in the CC group (10.6% vs. 4.9%, P<0.001).
Table 1.
Baseline characteristics of the included patients.
| Variable | Acalculous cholecystitis (n=539) | Calculous cholecystitis (n=3958) | P |
|---|---|---|---|
| Age, years, mean±SD | 53.6±18.1 | 49.2±15.4 | <0.001 |
| Sex, n (%) | 0.049 | ||
| Male | 280 (51.9) | 1873 (47.3) | |
| Female | 259 (48.1) | 2085 (52.7) | |
| BMI, kg/m2, mean±SD | 25.1±4.2 | 25.5±4.0 | 0.055 |
| Smoking, n (%) | 97 (18.0) | 720 (18.2) | 0.960 |
| Alcohol intake, n (%) | 166 (30.8) | 1194 (30.2) | 0.803 |
| Pregnancy, n (%) | 1 (0.2) | 7 (0.2) | >0.999 |
| Charlson comorbidity index | 0.4±0.8 | 0.3±0.7 | 0.004 |
| ASA, n (%) | 0.009 | ||
| Ⅰ | 207 (38.4) | 1797 (45.4) | |
| Ⅱ | 294 (54.5) | 1929 (48.7) | |
| Ⅲ | 38 (7.1) | 222 (5.6) | |
| Ⅳ | 0 (0.0) | 10 (0.3) | |
| Duration from symptom to admission, days, mean±SD | 3.3±3.9 | 4.0±4.5 | 0.001 |
| CT findings, n (%) | |||
| GB distention | 245 (45.5) | 1447 (36.6) | <0.001 |
| GB wall enhancement | 30 (5.6) | 230 (5.8) | 0.896 |
| GB wall thickening | 324 (60.1) | 2571 (65.0) | 0.031 |
| Pericholecystic enhancement | 115 (21.3) | 1088 (27.5) | 0.003 |
| Pericholecystic fluid collection | 92 (17.1) | 391 ( 9.9) | <0.001 |
| Presence of acute cholangitis, n (%) | 170 (31.5) | 1029 (26.0) | 0.007 |
| Performing ERCP, n (%) | 101 (18.7) | 711 (18.0) | 0.705 |
| PTGBD, n (%) | 57 (10.6) | 193 (4.9) | <0.001 |
| Duration from admission to cholecystectomy, days, mean±SD | 3.7±5.8 | 2.7±3.0 | <0.001 |
| Laboratory findings at 24 h after ERCP, median (IQR) | |||
| WBC, /μl | 8300.0 (6200.0–11 900.0) | 7300.0 (5700.0–10 000.0) | <0.001 |
| Hb, g/dl | 13.7 (12.5–14.9) | 13.8 (12.8–15.0) | 0.056 |
| Platelet, /μl | 244.0 (193.0–291.0) | 245.0 (204.0–291.0) | 0.112 |
| AST, IU/l | 26.0 (19.0–67.0) | 24.0 (18.0–52.0) | 0.016 |
| ALT, IU/l | 28.0 (16.0–66.0) | 24.0 (15.0–65.0) | 0.082 |
| GGT, g/dl | 79.0 (61.0–113.5) | 72.0 (57.0–101.0) | <0.001 |
| Total bilirubin, mg/dL | 42.0 (20.5–168.0) | 39.0 (19.0–148.0) | 0.252 |
| Amylase, IU/l | 0.7 (0.5–1.3) | 0.7 (0.4–1.1) | 0.022 |
| Lipase, U/l | 57.0 (42.0–77.0) | 59.0 (46.0–77.0) | 0.020 |
| CRP, mg/l | 28.0 (19.0–45.0) | 31.0 (22.0–46.0) | 0.006 |
| Used antibiotics, n (%) | <0.001 | ||
| 1st Cephalosporin | 0 (0.0) | 42 (1.1) | |
| 2nd Cephalosporin | 101 (18.7) | 906 (22.9) | |
| 3rd Cephalosporin | 268 (49.7) | 1897 (47.9) | |
| 3rd Cephalosporin + Aminoglycoside | 36 (6.7) | 531 (13.4) | |
| 3rd Cephalosporin + Metronidazole | 12 (2.2) | 51 (1.3) | |
| 4th Cephalosporin | 6 (1.1) | 23 (0.6) | |
| Carbapenem | 24 (4.5) | 87 (2.2) | |
| Penicillin | 78 (14.5) | 296 (7.5) | |
| Quinolone | 14 (2.6) | 125 (3.2) | |
ALT, alanine aminotransferase; ASA, American Society of Anesthesiologists classification; AST, aspartate aminotransferase; CRP, C-reactive protein; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; GB, gallbladder; GGT, gamma-glutamil transferase; Hb, haemoglobin; PTGBD, percutaneous gallbladder drainage; WBC, white blood cell count.
Comparison of clinical outcomes between acalculous and calculous cholecystitis
Table 2 presents the clinical outcomes of the two groups. The incidence of GBP was significantly higher in the AC group than in the CC group (5.6% vs. 1.0%, P<0.001). However, there was no significant difference in ICU admission rate and length of ICU stay between both groups. Anatomically, the fundus was the predominant site of perforation in both groups. Furthermore, Type II perforation was more prevalent than other perforation types in both groups. The incidence of gangrenous cholecystitis was higher in the AC group, leading to a correspondingly higher incidence of Grade II or III acute cholecystitis in this group. Laparoscopy-assisted cholecystectomy was the predominant surgical intervention in both categories; however, the AC group exhibited a significantly higher rate of conversion to open surgery. Regarding gallstone composition in the CC group, pigment stones were more frequently observed than cholesterol stones.
Table 2.
Comparison of clinical outcomes between acalculous and calculous cholecystitis.
| Variable | Acalculous cholecystitis (n=539) | Calculous cholecystitis (n=3958) | P |
|---|---|---|---|
| ICU admission, n (%) | 33 (6.1) | 182 (4.6) | 0.148 |
| ICU hospital stay, days, mean±SD | 5.3±7.9 | 3.6±3.4 | 0.248 |
| Gangrenous cholecystitis, n (%) | 87 (16.1) | 258 (6.5) | <0.001 |
| Grade of acute cholecystitis, n (%) | <0.001 | ||
| Grade I | 428 (79.4) | 3564 (90.0) | |
| Grade II | 103 (19.1) | 335 (8.5) | |
| Grade III | 8 (1.5) | 59 (1.5) | |
| GB perforation, n (%) | 30 (5.6) | 38 (1.0) | <0.001 |
| Sites of perforation, n (%) | <0.001 | ||
| Fundus | 20 (3.7) | 25 (0.6) | |
| Corpus | 8 (1.5) | 13 (0.3) | |
| Infundibulum | 0 (0.0) | 1 (0.0) | |
| Cystic duct | 2 (0.4) | 0 (0.0) | |
| Type of perforation, n (%) | <0.001 | ||
| Type I | 13 (2.4) | 13 (0.3) | |
| Type II | 16 (3.0) | 25 (0.6) | |
| Type III | 1 (0.2) | 0 (0.0) | |
| Type of cholecystectomy, n (%) | 0.001 | ||
| Laparoscopic assisted | 505 (93.7) | 3615 (91.3) | |
| Robot assisted | 24 (4.5) | 313 (7.9) | |
| Open conversion | 10 (1.9) | 30 (0.8) | |
| GB stone type, n (%) | |||
| Cholesterol stone | 0 (0.0) | 748 (18.9) | |
| Pigment stone | 0 (0.0) | 3210 (81.1) | |
| Postoperative complication, n (%) | 12 (2.2) | 39 (1.0) | 0.019 |
| Type of complication, n (%) | 0.009 | ||
| Small bowel obstruction | 2 (0.4) | 1 (0.0) | |
| Bile leakage | 3 (0.6) | 13 (0.3) | |
| Bleeding | 1 (0.2) | 3 (0.1) | |
| Hemoperitoneum | 1 (0.2) | 0 (0.0) | |
| OP site abscess | 3 (0.6) | 13 (0.3) | |
| Biliary stricture | 0 (0.0) | 2 (0.1) | |
| Vascular injury | 2 (0.4) | 5 (0.1) | |
| Wound infection | 0 (0.0) | 2 (0.1) | |
| GB cancer, n (%) | 2 (0.4) | 1 (0.0) | 0.043 |
| Disease-specific death, n (%) | 2 (0.4) | 3 (0.1) | 0.215 |
| Total hospital stay, days, mean±SD | 9.0±7.4 | 8.1±52.5 | 0.341 |
GB, gallbladder; ICU, intensive care unit.
Regarding postoperative complications, the AC group exhibited a significantly higher incidence of overall complications than the CC group (2.2% vs. 1.0%, P<0.001). Notably, the AC group had a higher frequency of small bowel obstruction by postoperative adhesions, bile leakage, abscess formation at the surgical site, biliary strictures, and vascular injury compared to that in the CC group. In addition, incidental GB malignancies were detected in two cases in the AC group compared with one case in the CC group. However, there was no significant difference in disease-specific mortality rate or overall duration of hospital stay between the two groups.
In an additional analysis of the total cohort, which included surgically unfit patients who had not undergone cholecystectomy (SDC, Table S1, Supplemental Digital Content 2, http://links.lww.com/JS9/B542), it was observed that the proportions of GBP, ICU admission, and disease-specific mortality were significantly higher in the conservative treatment group compared to the cholecystectomy group. Conversely, the presence of GB stones, concurrent cholangitis, and the incidence of gangrenous cholecystitis were notably higher in the cholecystectomy group. Additionally, total hospital stay and ICU stay were significantly longer in the conservative treatment group compared to the cholecystectomy group.
Risk factors for the development of GBP
Table 3 presents the factors contributing to the development of GBP. The initial univariate analysis indicated several notable variables, as follows. Age ≥60 years was identified as a significant risk factor, with an odds ratio (OR) of 5.04 and a 95% CI of 3.08–8.45. Male sex was also identified as a significant risk factor (OR: 2.85, 95% CI: 1.70–4.97). Other notable factors included an abnormal CCI [OR: 3.03 (1.85–4.76)], an ASA classification at level II or higher (OR: 2.44 [1.44–4.36]), the presence of simultaneous acute cholangitis [OR: 4.29 (2.64–7.08)], and AC [OR: 6.25 (3.70–10.00)]. However, after adjusting for potential confounding variables, a refined analysis indicated that patients with AC are at a significantly higher risk of developing GBP than those with CC (OR: 5.00, 95% CI: 2.94–8.33). In addition, age ≥60 years remains a significant risk factor [OR, 2.60 (1.49–4.63)]. Other confirmed risk factors were male sex [OR: 2.55 (1.48–4.57)] and the incidence of coexisting acute cholangitis [OR: 2.84 (1.71–4.80)].
Table 3.
Risk of GB stones for the development of GB perforation.
| Univariable analysis | Multivariable analysis | |||||
|---|---|---|---|---|---|---|
| Variable | N | Perforation, n (%) | OR (95% CI) | P | OR (95% CI) | P |
| Age | ||||||
| <60 years | 3272 | 24 (0.7) | 1 | 1 | ||
| ≥60 years | 1225 | 44 (3.6) | 5.04 (3.08–8.45) | <0.001 | 2.60 (1.49–4.63) | <0.001 |
| Sex | ||||||
| Female | 2344 | 19 (0.8) | 1 | 1 | ||
| Male | 2153 | 49 (2.3) | 2.85 (1.70–4.97) | <0.001 | 2.55 (1.48–4.57) | 0.001 |
| Normal (BMI 18.5–24.9) | 1148 | 24 (2.1) | 1 | 1 | ||
| Overweight (BMI 25.0–29.9) | 961 | 15 (1.6) | 1.35 (0.71–2.64) | 0.370 | ||
| Obese (BMI ≥30) | 2295 | 28 (1.2) | 0.78 (0.42–1.50) | 0.438 | ||
| Underweight (BMI <18.5) | 93 | 1 (1.1) | 0.69 (0.04–3.44) | 0.716 | ||
| Smoker | 817 | 8 (1.0) | 0.60 (0.26–1.18) | 0.172 | 0.50 (0.21–1.06) | 0.090 |
| Alcohol intake | 1360 | 19 (1.4) | 0.89 (0.51–1.50) | 0.677 | ||
| Abnormal CCI | 953 | 30 (3.1) | 3.03 (1.85–4.76) | <0.001 | 1.44 (0.79–2.63) | 0.234 |
| ASA II or higher | 2493 | 51 (2.0) | 2.44 (1.44–4.36) | 0.002 | 1.23 (0.62–2.45) | 0.558 |
| Duration from Symptom to admission (>4 days) | 1617 | 19 (1.2) | 0.69 (0.39–1.15) | 0.168 | 0.94 (0.53–1.60) | 0.821 |
| Acute cholangitis | 1199 | 41 (3.4) | 4.29 (2.64–7.08) | <0.001 | 2.84 (1.71–4.80) | <0.001 |
| Acalculous cholecystitis | 539 | 30 (5.6) | 6.25 (3.70–10.00) | <0.001 | 5.00 (2.94–8.33) | <0.001 |
ASA, American Society of Anesthesiologists classification; CCI, Charlson Comorbidity Index; GB, gallbladder.
A logistic regression analysis was performed to determine the association between the presence of gallstones and the incidence of gangrenous cholecystitis (SDC, Table S2, Supplemental Digital Content 2, http://links.lww.com/JS9/B542). The results showed several independent risk factors for the incidence of gangrenous cholecystitis, including AC, age older than or equal to 60 years, male sex, an anomalous CCI, a protracted duration (>4 days) from the initial symptom presentation to hospital admission, and the concurrent manifestation of acute cholangitis. Furthermore, a distinct group of eight patients radiologically diagnosed with GBP underwent endoscopic transpapillary GB drainage (ETGBD) or PTGBD. This alternative treatment modality was selected because the patients’ conditions were deemed unsuitable for surgical intervention (SDC, Table S3, Supplemental Digital Content 2, http://links.lww.com/JS9/B542).
In a comparative analysis according to GBP, GB stones were more frequently found in the no GBP group than in the GBP group (SDC, Table S4, Supplemental Digital Content 2, http://links.lww.com/JS9/B542). However, other clinical outcome-related variables, including the proportion of ICU admission, and postoperative complications were significantly higher in the GBP group than in the no GBP group. In addition, duration from symptom and admission to cholecystectomy were both significantly longer in the GBP group than in the no GBP group.
Clinical outcomes according to the timing of cholecystectomy
Table 4 presents the clinical outcomes based on the timing of cholecystectomy. Patients were divided into two groups: those who underwent early cholecystectomy (EC) within 24 h of arrival and those who underwent delayed cholecystectomy (DC) after the initial 24-h period post-arrival. The time interval from the onset of symptoms to cholecystectomy was significantly shorter in the EC group than in the DC group (5.8±4.9 vs. 7.4±5.4 days, P<0.001), while the time interval from the onset of symptoms to admission was significantly longer in the EC group than in the DC group (4.9±4.9 vs. 3.0±3.8 days, P<0.001). Notably, the DC group had a significantly higher prevalence of GBP than the EC group (2.0% vs. 0.9%, P<0.001). In addition, patients in the DC group had a higher frequency of ICU admission, extended length of ICU stay, higher incidence of gangrenous cholecystitis, and a greater burden of overall complications. Five disease-specific mortalities occurred in the DC group; however, this metric did not show a statistically significant difference between the two groups.
Table 4.
Clinical outcomes categorized by timeframe of surgical intervention.
| Variable | Early cholecystectomy (<24 h) (n=2126) | Delayed cholecystectomy (≥24 h) (n=2371) | P |
|---|---|---|---|
| Duration from symptom to admission, days, mean±SD | 4.9±4.9 | 3.0±3.8 | <0.001 |
| Duration from symptom to cholecystectomy, days, mean±SD | 5.8±4.9 | 7.4±5.4 | <0.001 |
| ICU admission, n (%) | 30 (1.4) | 185 (7.8) | <0.001 |
| ICU hospital stay, days, mean±SD | 2.8±1.2 | 4.0±4.7 | 0.004 |
| Gangrenous cholecystitis, n (%) | 95 (4.5) | 250 (10.5) | <0.001 |
| Grade of acute cholecystitis, n (%) | <0.001 | ||
| Grade I | 2004 (94.3) | 1988 (83.8) | |
| Grade II | 115 (5.4) | 323 (13.6) | |
| Grade III | 7 ( 0.3) | 60 (2.5) | |
| GB perforation, n (%) | 20 (0.9) | 48 (2.0) | 0.004 |
| Type of perforation, n (%) | 0.011 | ||
| Type I | 5 (0.2) | 21 (0.9) | |
| Type II | 15 (0.7) | 26 (1.1) | |
| Type III | 0 (0.0) | 1 (0.0) | |
| Postoperative complication, n (%) | 16 (0.8) | 35 (1.5) | 0.032 |
| Type of complication, n (%) | 0.103 | ||
| Small bowel obstruction | 0 (0.0) | 3 (0.1) | |
| Bile leakage | 5 (0.2) | 11 (0.5) | |
| Bleeding | 1 (0.0) | 3 (0.1) | |
| Hemoperitoneum | 0 (0.0) | 1 (0.0) | |
| OP site abscess | 7 (0.3) | 9 (0.4) | |
| Biliary stricture | 0 (0.0) | 2 (0.1) | |
| Vascular injury | 1 (0.0) | 6 (0.3) | |
| Wound infection | 2 (0.1) | 0 (0.0) | |
| Disease-specific death, n (%) | 0 (0.0) | 5 (0.2) | 0.095 |
| Total hospital day, days, mean±SD | 5.1±1.7 | 11.1±67.7 | <0.001 |
GB, gallbladder; ICU, intensive care unit.
Discussion
To the best of our knowledge, the present study is the largest of its kind to retrospectively analyze the association between gallstones and the development of GBP in patients who underwent cholecystectomy. Herein, we found that AC is a significant risk factor for developing GBP compared with CC. Therefore, the present study’s results can directly impact patient care, especially in terms of patient counselling, monitoring, and surgical decision-making. Notably, knowing that patients with AC are at a higher risk of developing GBP might influence the decision to operate earlier in certain cases, although the duration from initial symptoms to admission is not an independent risk factor for developing GBP. In the present study, ~12% of the included patients had AC. However, the clinical impact of AC should be considered because it is a significant risk factor for the development of GBP and is found in a significant proportion of patients.
Of the 4497 patients with acute cholecystitis, 68 (1.5%) developed GBP, including 30 (5.6%) in the AC group and 38 (1.0%) in the CC group. Historically, the incidence of GBP was much higher, especially before laparoscopic cholecystectomy became the standard treatment for acute cholecystitis. In older literature14–17, the incidence of GBP was reported to be ~10% among patients with acute cholecystitis. Recent studies5,18,19 have shown that the incidence of GBP among patients with acute cholecystitis ranges from 2 to 11%. In contrast to previous reports, our 10-year experience showed that the incidence of GBP has decreased with advances in medical imaging, early diagnosis, and treatment modalities. Similarly, a more recent study conducted by Stefanidis and colleagues reported that the incidence of GBP was 0.8% (30 of 3752 patients) in a group of patients with acute cholecystitis. This percentage was significantly lower than the 2–15% reported in most published studies15–17. These observed differences might be due to regional disparities. Another plausible explanation is a shift in therapeutic strategies in contemporary medicine. Recent trends indicate a higher frequency of cholecystectomies for symptomatic cholelithiasis than historical practices20,21. Current research suggests that a significant proportion of patients diagnosed with GBP exhibit symptoms associated with GB in earlier stages22,23. Theoretically, timely medical interventions might have prevented these subsequent perforations. This perspective is further corroborated by historical data that indicate a steady decline in GBP incidence since the first documented cases in the 1940s.
A salient observation from the present study was that the duration from the initial manifestation of symptoms to subsequent hospital admission did not correlate with the risk of developing GBP. The present study’s results are compelling and may challenge the prevailing notion that a postponed diagnosis and intervention in cases of acute cholecystitis increase the risk of developing GBP9. The present study’s suggestion that the time interval from the initiation of symptoms to hospital admission does not significantly influence the development of GBP is provocative. However, it is vital to analyze these findings considering the study’s limitations and a more comprehensive perspective on GBP. The present study may not have accounted for other potential contributors to the risk of perforation. The absence of a relationship between admission delay and GBP might be attributed to diverse variables such as disease intensity, distinct patient responses, and the calibre of medical treatment provided.
However, the present study’s results highlight the importance of early surgical intervention in patients suspected of GBP. We observed a significant difference in the outcomes based on the timing of cholecystectomy after admission. Patients who underwent EC experienced fewer complications and a shorter postoperative length of hospital stay or even ICU length of stay than those who underwent DC; however, the decision for EC might be influenced by multiple factors, including the medical team’s strategy for managing acute cholecystitis and patient-specific conditions. In a recent study by Blohm et al., surgery performed within 2 days of admission had the best outcomes, and waiting more than 4 days after admission before performing the surgery increased risks such as bile duct injuries, mortality within 30 and 90 days, and more complications during and after surgery24. Therefore, the present study suggests that early surgical intervention, within 24 h of admission, is associated with improved outcomes in terms of reduced complications and shorter hospital stays. Considering the time interval from the onset of symptoms to cholecystectomy, it was significantly shorter in the EC group than in the DC group, although the time interval from the onset of symptoms to admission was significantly longer in the EC group than in the DC group. These results solidify the conclusion that early surgical intervention after admission can significantly diminish acute cholecystitis-related morbidity and mortality, including GBP.
This study had some limitations. First, because this study was not a randomized controlled trial, incomplete data collection and selection bias may have been present, even though we diligently gathered accurate information through extensive medical chart reviews. Second, this study was conducted in a single university-affiliated centre in South Korea, which may limit the generalizability of our findings to multicenter studies in other countries. Finally, the diagnosis of GBP was primarily established through operative findings, excluding patients who were not operated on, potentially leading to an underestimation of cases in which the disease remained undiagnosed. Notably, other treatment modalities, such as PTGBD or ETGBD, were employed, and surgery was not subsequently pursued.
In conclusion, this study provides a better understanding of the role of AC as a risk factor for the development of GBP. AC is a significant risk factor for developing GBP. The incidence of GBP is relatively low; however, its implications are severe, warranting a high degree of suspicion, especially in high-risk patients such as those with AC. Furthermore, early surgical intervention can significantly reduce GBP-related morbidity and mortality associated. Therefore, within our clinical practice, it is imperative that we prioritize patients with AC and expedite their management.
Ethical approval
The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the Ethics Committee at Hallym University Dongtan Sacred Heart Hospital (IRB no. 2022-04-008).
Consent
Due to the study’s retrospective design, the requirement for informed consent was waived.
Sources of funding
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT: Ministry of Science and ICT) (No. 2022R1C1C1006242). This research was supported by Hallym University Research Fund, 2023(HURF-2023-12).
Author contribution
S.W.P.: study concept; S.W.P.: study design; D.H.P., H.W.C., A.C., D.H.K., J.L., J.M.L., C.H.P. data acquisition; S.W.P., K.J.L., C.H.P.: data analysis and interpretation; S.W.P., C.H.P.: statistical analysis; S.W.P., K.J.L.: manuscript preparation; all: manuscript review.
Conflicts of interest disclosure
The authors have no potential conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Research registration unique identifying number
None.
Guarantor
Professor Se Woo Park.
Data availability statement
The data that support the findings of this study are available on request from the corresponding author, [S.W.P.]. The data are not publicly available due to restrictions of their containing information that could compromise the privacy of research participants.
Supplementary Material
Footnotes
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.lww.com/international-journal-of-surgery.
Published online 11 December 2023
Contributor Information
Kyong Joo Lee, Email: kyongjoolee1214@gmail.com.
Se Woo Park, Email: mdsewoopark@gmail.com.
Da Hae Park, Email: dahaepark82@gmail.com.
Hye Won Cha, Email: gpdnjsck@naver.com.
Ana Choi, Email: mm1550@naver.com.
Dong Hee Koh, Email: dhkoh@hallym.or.kr.
Jin Lee, Email: jinlee@hallym.or.kr.
Jung Min Lee, Email: jungmin012@hallym.or.kr.
Chan Hyuk Park, Email: yesable7@gmail.com.
References
- 1. Yokoe M, Hata J, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholecystitis (with videos). J Hepatobiliary Pancreat Sci 2018;25:41–54. [DOI] [PubMed] [Google Scholar]
- 2. Date RS, Thrumurthy SG, Whiteside S, et al. Gallbladder perforation: case series and systematic review. Int J Surg 2012;10:63–68. [DOI] [PubMed] [Google Scholar]
- 3. Derici H, Kara C, Bozdag AD, et al. Diagnosis and treatment of gallbladder perforation. World J Gastroenterol 2006;12:7832–7836. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Ausania F, Guzman Suarez S, Alvarez Garcia H, et al. Gallbladder perforation: morbidity, mortality and preoperative risk prediction. Surg Endosc 2015;29:955–960. [DOI] [PubMed] [Google Scholar]
- 5. Wang AJ, Wang TE, Lin CC, et al. Clinical predictors of severe gallbladder complications in acute acalculous cholecystitis. World J Gastroenterol 2003;9:2821–2823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Stefanidis D, Sirinek KR, Bingener J. Gallbladder perforation: risk factors and outcome. J Surg Res 2006;131:204–208. [DOI] [PubMed] [Google Scholar]
- 7. de Mestral C, Rotstein OD, Laupacis A, et al. Comparative operative outcomes of early and delayed cholecystectomy for acute cholecystitis: a population-based propensity score analysis. Ann Surg 2014;259:10–15. [DOI] [PubMed] [Google Scholar]
- 8. Roslyn JJ, DenBesten L, Thompson JE, Jr, et al. Roles of lithogenic bile and cystic duct occlusion in the pathogenesis of acute cholecystitis. Am J Surg 1980;140:126–130. [DOI] [PubMed] [Google Scholar]
- 9. Gallaher JR, Charles A. Acute cholecystitis: a review. JAMA 2022;327:965–975. [DOI] [PubMed] [Google Scholar]
- 10. Adachi T, Eguchi S, Muto Y. Pathophysiology and pathology of acute cholecystitis: a secondary publication of the Japanese version from 1992. J Hepatobiliary Pancreat Sci 2022;29:212–216. [DOI] [PubMed] [Google Scholar]
- 11. Laurila J, Syrjala H, Laurila PA, et al. Acute acalculous cholecystitis in critically ill patients. Acta Anaesthesiol Scand 2004;48:986–991. [DOI] [PubMed] [Google Scholar]
- 12. Bhattacharjee HK, Kaviyarasan MP, Singh KJ, et al. Age adjusted Charlson comorbidity index (a-CCI) AS a tool to predict 30-day post-operative outcome in general surgery patients. ANZ J Surg 2023;93:132–138. [DOI] [PubMed] [Google Scholar]
- 13. Mathew G, Agha R, Albrecht J, et al. STROCSS 2021: Strengthening the reporting of cohort, cross-sectional and case-control studies in surgery. Int J Surg 2021;96:106165. [DOI] [PubMed] [Google Scholar]
- 14. Menakuru SR, Kaman L, Behera A, et al. Current management of gall bladder perforations. ANZ J Surg 2004;74:843–846. [DOI] [PubMed] [Google Scholar]
- 15. Schneider JH, Lepsien G. Pathogenesis and therapy of gallbladder perforation. Zentralbl Chir 1988;113:1377–1387. [PubMed] [Google Scholar]
- 16. Larmi TK, Kairaluoma MI, Junila J, et al. Perforation of the gallbladder. A retrospective comparative study of cases from 1946-1956 and 1969-1980. Acta Chir Scand 1984;150:557–560. [PubMed] [Google Scholar]
- 17. Felice PR, Trowbridge PE, Ferrara JJ. Evolving changes in the pathogenesis and treatment of the perforated gallbladder. a combined hospital study. Am J Surg 1985;149:466–473. [DOI] [PubMed] [Google Scholar]
- 18. Sood BP, Kalra N, Gupta S, et al. Role of sonography in the diagnosis of gallbladder perforation. J Clin Ultrasound 2002;30:270–274. [DOI] [PubMed] [Google Scholar]
- 19. Bennett GL, Balthazar EJ. Ultrasound and CT evaluation of emergent gallbladder pathology. Radiol Clin North Am 2003;41:1203–1216. [DOI] [PubMed] [Google Scholar]
- 20. Escarce JJ, Chen W, Schwartz JS. Falling cholecystectomy thresholds since the introduction of laparoscopic cholecystectomy. JAMA 1995;273:1581–1585. [PubMed] [Google Scholar]
- 21. Legorreta AP, Silber JH, Costantino GN, et al. Increased cholecystectomy rate after the introduction of laparoscopic cholecystectomy. JAMA 1993;270:1429–1432. [PubMed] [Google Scholar]
- 22. Roslyn JJ, Thompson JE, Jr, Darvin H, et al. Risk factors for gallbladder perforation. Am J Gastroenterol 1987;82:636–640. [PubMed] [Google Scholar]
- 23. Tsai CJ, Wu CS. Risk factors for perforation of gallbladder. A combined hospital study in a Chinese population. Scand J Gastroenterol 1991;26:1027–1034. [DOI] [PubMed] [Google Scholar]
- 24. Blohm M, Osterberg J, Sandblom G, et al. The Sooner, the Better? The Importance of Optimal Timing of Cholecystectomy in Acute Cholecystitis: Data from the National Swedish Registry for Gallstone Surgery, GallRiks. J Gastrointest Surg 2017;21:33–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author, [S.W.P.]. The data are not publicly available due to restrictions of their containing information that could compromise the privacy of research participants.