International Journal of Surgery 17 (2015) 5e9
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Original research
Augmenting the decision making process in acute appendicitis: A retrospective cohort study M.A. Abdelhalim a, b, *, J.D.A. Stuart a, b, G.A. Nicholson a, b a b
Western Infirmary Glasgow, NHS Greater Glasgow & Clyde, UK University of Glasgow, Glasgow, UK
h i g h l i g h t s Pre-operative investigation in acute appendicitis is analysed. Elevated WCC and CRP are sensitive but non-specific markers in acute appendicitis. Elevated serum bilirubin is a specific but insensitive marker in acute appendicitis. CT scanning reduces negative appendicectomy rate to 1%. Ultrasound scanning does not reduce negative appendicectomy rate.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 December 2014 Received in revised form 23 February 2015 Accepted 5 March 2015 Available online 14 March 2015
Introduction: Acute appendicitis is a common surgical diagnosis. We investigated the use of blood markers (WCC, CRP and serum bilirubin) and diagnostic imaging (USS and CT scan) to arrive at this diagnosis, as well as the surgical approach used for appendicectomy. Methods: This was a retrospective analysis of consecutive patients undergoing appendicectomy in seven hospitals within GG&C Health Board during a 6 month study period. Data were collected from electronic patient records. Sensitivity and specificity of each investigation for diagnosing acute appendicitis was calculated. Results: 363 patients were included. Appendicectomy was performed open in 53%, laparoscopically in 43% and converted in 4%. Diagnostic imaging was used in 38%. The overall negative appendicectomy rate was 15% (18% when no imaging was used, 23% when USS was used and 1% when CT scanning was used). Elevated bilirubin had a sensitivity of 0.44 and a specificity of 0.84 for detecting acute appendicitis. Sensitivity and specificity for elevated WCC were 0.78 and 0.55, and for elevated CRP were 0.81 and 0.59, respectively. The specificity of bilirubin for diagnosing perforated appendicitis was 0.63. Discussion: WCC and CRP were sensitive blood markers in acute appendicitis, whereas serum bilirubin was more specific. Diagnostic imaging with a CT scan was very effective at reducing the rate of negative appendicectomy, but USS was not. Conclusion: Serum bilirubin has utility in diagnosing acute appendicitis, irrespective of whether perforation has occurred. CT scanning should be considered the first line imaging modality for investigation of acute appendicitis if diagnosis is in doubt. © 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Appendicitis Appendicectomy Appendectomy Diagnosis Bilirubin Hyperbilirubinaemia CRP White cell count CT scan Ultrasound scan Laparoscopic
1. Introduction Acute appendicitis is a common surgical emergency. However, the differential diagnosis is wide, especially in females. Mesenteric adenitis, ovarian pathologies, mittelschmerz, pelvic inflammatory
* Corresponding author. Western Infirmary Glasgow, Dumbarton Road, G11 6NT Glasgow, UK. http://dx.doi.org/10.1016/j.ijsu.2015.03.004 1743-9191/© 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
disease and inflammatory bowel disease are all possible causes of right iliac fossa pain. This diagnostic conundrum has been appreciated for many years. Additional biochemical investigations have long been used to compliment the clinical diagnosis [1]. The main investigations in current use are blood inflammatory markers, namely white cell count (WCC) and C-reactive protein (CRP), as well as the imaging modalities of abdominal ultrasound scan (USS) and computed tomography (CT) scan. More recently, serum
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M.A. Abdelhalim et al. / International Journal of Surgery 17 (2015) 5e9
bilirubin has been shown to be a more specific marker for acute appendicitis, especially when perforation is more likely [2e5]. The pathophysiology of this bilirubin rise is unclear. It may be that with inflammation and infection of the appendix, especially if there is perforation, bacteria are allowed to enter the portal circulation. These bacteria would then arrive at the liver and if the load is high enough to overwhelm the Kupffer cell function of the liver, a degree of hepatocyte damage may occur, which would be reflected as a rise in serum bilirubin [6]. A negative appendicectomy has the drawbacks of exposing the patient to unnecessary surgery and delaying the definitive diagnosis, as well as incurring unnecessary financial cost. The overall rate of negative appendicectomy is reducing. This could be attributed to better diagnostics [7]. It does however remain a common problem that general surgeons strive to avoid. Any appropriate test that can increase the accuracy of diagnosis is therefore valuable. The open appendicectomy for treatment of acute appendicitis is an old operation, with the popular McBurney incision being described in 1894 [8]. Although the open approach remains entirely valid, there has been a recent move to the more modern laparoscopic approach, especially in women [9]. There are conflicting opinions about whether open or laparoscopic appendicectomy should be favoured routinely and it seems that both approaches are equally safe and effective in experienced hands [10e14]. The study aims to examine the current utilisation of preoperative investigations to diagnose acute appendicitis. The value of the blood markers WCC, CRP and serum bilirubin as well as the imaging modalities of abdominal USS and CT scan in diagnosing acute appendicitis and avoiding negative appendicectomy will be investigated.
2. Methods This was a retrospective analysis of 500 consecutive patients undergoing appendicectomy in seven hospitals within the Greater Glasgow & Clyde Health Board from 19/09/2012 to 05/03/2013. Data were collected from the electronic patient records through the health board Clinical Portal system. Inclusion criteria were then applied to select the appropriate patient group (Fig. 1). Baseline demographics were recorded for each patient including age, sex, date of operation and hospital. Blood results were reviewed. The white cell count (WCC), C-reactive protein (CRP) and serum bilirubin results on admission were noted. According to local laboratory reference ranges, elevated WCC was taken to be greater than 10.0 109/L. Elevated CRP was greater than 10 mg/L and elevated serum bilirubin was greater than 20 mmol/L. Radiology reports were examined to investigate the use of imaging in the diagnosis of acute appendicitis. Pathology reports were also read to ascertain the final diagnosis. This was recorded as normal appendix, simple acute appendicitis, or acute appendicitis with perforation. The operative approach was obtained from examination of the operative notes. Biochemical, histopathological and radiological variables were correlated and statistical analysis was then performed using SPSS
version 22 [15]. Clinical details on admission were not collected or used in the analysis. However, at the time of operation, all patients in this study had a clinical diagnosis of acute appendicitis. Baseline blood tests were performed in all patients on admission. There is no institutional policy on the use of imaging for acute appendicitis and therefore, when imaging was used, it was due to uncertainty over the diagnosis.
3. Results The patient records of 500 consecutive patients undergoing appendicectomy for suspected acute appendicitis in the Greater Glasgow & Clyde Health Board between 19/09/12 and 05/03/2013 were examined. The inclusion criteria were met by 363 patients, who were included in the analysis (Fig. 1). Of these patients, 226 (62%) were male and 137 (38%) were female. The age range was 3e86 years. Mean age was 31 years. Pre-operative diagnostic imaging was utilised in 137 (38%) patients. An USS only was performed in 58 (16%) patients and a CT scan only was performed in 71 (20%) patients. Eight patients (2%) were imaged with both USS and CT scan. Of the female patients, 53% had pre-operative diagnostic imaging, compared to only 28% of male patients (p < 0.005). There was also a gender difference in the chosen modality of imaging, with a CT scan being performed in 72% of males imaged compared to 40% of females imaged, where ultrasound scan was favoured (Table 1). The negative appendicectomy rate in patients who did not have any pre-operative imaging was 18%, compared to 23% in patients who had an USS and 1% in those who had a CT scan (Table 2). Statistical analysis showed that performance of a CT scan significantly increased the accuracy of diagnosis (p < 0.005), whereas USS did not. Operative data were available for 306 patients in the study. Of these patients, 162 (53%) had an open appendicectomy and 132 (43%) had a laparoscopic appendicectomy. The remaining 12 (4%) patients had the procedure started laparoscopically, then converted to open. A laparoscopic approach was favoured in females and was attempted first in 74%. This compares to only 31% of males, creating a significant gender difference in the choice of approach (p < 0.005). Table 3 illustrates the operative approach used by gender. Pathology results were reviewed for all 363 patients in the study. In 56 (15%) cases, the appendix was found to be normal. Appendicitis without perforation was diagnosed in 254 (70%) cases and perforated appendicitis was found in 53 (15%) patients. Bilirubin, WCC and CRP levels were compared to pathology, as summarised in (Table 4). There was a significant rise in all three blood markers in patients with acute appendicitis (p < 0.005). There was also a significant difference in the levels of all blood markers between those with simple appendicitis and those with perforated appendicitis (p < 0.005). When a standard laboratory reference range was used, an elevated bilirubin had a sensitivity of 0.44 and a specificity of 0.84 for detecting acute appendicitis. Meanwhile, an elevated WCC had a sensitivity of 0.78 and specificity of 0.55. Elevated CRP had a sensitivity of 0.81 and specificity of 0.59. Positive predictive value and negative predictive value were also calculated for each of the
Table 1 Pre-operative diagnostic imaging and gender.
Fig. 1. Inclusion criteria.
Male Female
Ultrasound scan
CT scan
No imaging
19 (8%) 47 (34%)
48 (21%) 31 (23%)
162 (72%) 64 (47%)
M.A. Abdelhalim et al. / International Journal of Surgery 17 (2015) 5e9 Table 2 Pre-operative diagnostic imaging and negative appendicectomy rate.
Normal Appendix Acute Appendicitis
Ultrasound scan
CT scan
No imaging
15 (23%) 51 (77%)
1 (1%) 78 (99%)
40 (18%) 186 (82%)
Table 3 Operative approach and gender.
Male Female
Open
Laparoscopic
Conversion
132 (69%) 30 (26%)
53 (28%) 79 (69%)
7 (3%) 5 (5%)
Table 4 Blood markers and pathology.
Elevated Bilirubina Elevated WCCa Elevated CRPa
Normal appendix (n ¼ 56)
Appendicitis without perforation (n ¼ 254)
Perforated appendicitis (n ¼ 53)
9 25 23
106 192 201
28 48 49
a According to local laboratory reference ranges, elevated WCC 10.0 109/L, elevated CRP 10 mg/L, and elevated serum bilirubin 20 mmol/L.
blood markers. Bilirubin had the highest PPV while CRP had the highest NPV (Table 5). The same analysis was performed separately for the subgroup of patients who did not undergo diagnostic imaging in order to assess the utility of these blood markers in the absence of imaging. There was no significant difference in the sensitivity, specificity, PPV or NPV of any of these blood markers for detecting acute appendicitis in this patient group (Table 6). When only cases of perforated appendicitis were considered, an elevated bilirubin had a sensitivity of 0.53 and specificity of 0.63; PPV was 0.20 and NPV was 0.63. By comparison, elevated WCC had a sensitivity of 0.91 and specificity of 0.30, while elevated CRP had a sensitivity of 0.92 and specificity of 0.28. 4. Discussion Acute appendicitis is a common surgical diagnosis. We investigated the use of blood markers and diagnostic imaging to arrive at this diagnosis, as well as the surgical approach used for appendicectomy in our large population.
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rate to 1% when patients were imaged by CT scan. USS did not improve diagnostic accuracy. These figures are comparable to a study by Zoarets et al. who demonstrated a negative appendicectomy rate of 18.8% with a CT utilisation rate of 35.2% [16]. This diagnostic approach illustrated by the current study is in contrast to the centres in Seoul, Korea, where imaging utilisation rate was 99.7% and overall negative appendicectomy rate was 4.1% [17]. It is evident that increasing use of imaging, particularly CT scanning, can improve diagnostic accuracy and reduce the rate of negative appendicectomy. This has to be balanced with the well documented radiation risks of imaging and decisions should be made after considering both the risks and the benefits [18]. Perhaps limited range CT scanning can be used to limit radiation exposure yet maintain diagnostic accuracy [19]. Pre-operative diagnostic imaging was almost twice as likely to be utilised in female patients than in males in the current study. This is perhaps due to the greater diagnostic uncertainty in females with right iliac fossa pain such as the possibility of ovarian pathology. Female patients were more likely to be imaged with USS while CT scanning was more widely utilised in males. Similar findings have previously been documented [20]. This may be due to a greater caution taken with radiation risk in young females. 4.2. Approach Laparoscopic appendicectomy was the operation of choice in 47% of patients in our study group. In 4% of patients, the operation was converted to an open procedure and so the rate of completed laparoscopic appendicectomy was 43%. In many centres there is a general trend towards a laparoscopic approach for appendicectomy [9]. Extensive evidence is available to support the safety of laparoscopic appendicectomy for both simple and complicated appendicitis [10e12]. Other studies have highlighted the added cost of laparoscopic appendicectomy for little or no added benefit [14]. Ultimately, the choice of surgical approach depends on the local institution, the surgeon's experience and patient preference [13]. The current data show a significant difference in operative approach between genders with laparoscopy being chosen in 74% of females compared to only 31% of males (Table 3). The reasons behind this difference were not investigated in the study. However, it may be that the greater diagnostic uncertainty in females leads surgeons to favour diagnostic laparoscopy, which then proceeds to laparoscopic appendicectomy in some cases. It is also possible that the scar of an open appendicectomy is less acceptable in female patients than in males. 4.3. Blood markers
4.1. Diagnostic imaging Despite modern imaging techniques, appendicitis remains a clinical diagnosis in the first instance. Other tests are used as adjuncts. This is highlighted by the finding that the majority of patients in the study group (62%) proceeded to surgery without any diagnostic imaging. However, the current data show that the negative appendicectomy rate in patients who did not undergo diagnostic imaging is 18%. There was a significant reduction in this
The levels of WCC, CRP and bilirubin were all associated significantly with degree of inflammation in appendicitis. A rise in all blood markers was seen in simple appendicitis, and a greater rise was seen in perforated appendicitis. The use of WCC and CRP as inflammatory markers is long standing and although sensitive, these markers are not specific for acute appendicitis. Recently, a wealth of evidence has accumulated for the use of serum bilirubin as a specific marker in acute appendicitis and especially perforated
Table 5 Sensitivity and specificity of blood markers for detecting acute appendicitis.
Elevated Bilirubina Elevated WCCa Elevated CRPa a
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
0.44 (0.38e0.49) 0.78 (0.73e0.83) 0.81 (0.77e0.86)
0.84 (0.71e0.92) 0.55 (0.42e0.68) 0.59 (0.45e0.72)
0.94 (0.88e0.97) 0.91 (0.86e0.94) 0.92 (0.87e0.94)
0.21 (0.16e0.27) 0.32 (0.23e0.42) 0.37 (0.27e0.48)
According to local laboratory reference ranges, elevated WCC 10.0 109/L, elevated CRP 10 mg/L, and elevated serum bilirubin 20 mmol/L.
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M.A. Abdelhalim et al. / International Journal of Surgery 17 (2015) 5e9
Table 6 Sensitivity and specificity of blood markers for detecting acute appendicitis in patients who did not undergo diagnostic imaging.
Elevated Bilirubina Elevated WCCa Elevated CRPa a
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
0.42 (0.35e0.49) 0.81 (0.74e0.86) 0.80 (0.73e0.85)
0.83 (0.67e0.92) 0.55 (0.39e0.70) 0.60 (0.43e0.75)
0.92 (0.83e0.96) 0.89 (0.83e0.93) 0.90 (0.84e0.94)
0.23 (0.17e0.31) 0.38 (0.26e0.52) 0.39 (0.27e0.53)
According to local laboratory reference ranges, elevated WCC 10.0 109/L, elevated CRP 10 mg/L, and elevated serum bilirubin 20 mmol/L.
appendicitis [2e5]. The current study demonstrated that an elevated bilirubin has a specificity of 0.84 and positive predictive value of 0.94 for acute appendicitis, higher than both WCC and CRP. However, its sensitivity was low at only 0.44 (Table 5). When only cases of perforated appendicitis were considered, it was found that the specificity of an elevated bilirubin was only 0.63 and the PPV was 0.20. These results are in contrast to previous studies which advocated the use of serum bilirubin to detect acute appendicitis with perforation [2,4]. The results of the current study support the use of bilirubin as a novel diagnostic marker in cases of suspected acute appendicitis, and if noted to be high in these cases suspicion should certainly be raised. It should be used with caution however, as our data suggest that serum bilirubin may be normal in over half of cases of acute appendicitis. At best, serum bilirubin is a useful adjunctive diagnostic marker. In detecting cases where perforation had occurred, we found that serum bilirubin was a poor predictive marker and therefore we would not recommend its use in identifying these cases. Gilbert's syndrome is a genetic liver disorder affecting up to 6% of the population that causes a rise in serum bilirubin [21]. No effort was made to trace and exclude these patients from the study. However, given the number of patients in the study, it is unlikely that this confounding factor would affect the overall conclusions. 5. Conclusion In this retrospective study we investigated the use of preoperative blood markers and imaging in aiding the diagnosis of acute appendicitis. We also examined the surgical approach to appendicectomy in our region. WCC and CRP were sensitive blood markers, whereas serum bilirubin was the most specific blood marker in acute appendicitis. Diagnostic imaging with a CT scan was very effective at reducing the rate of negative appendicectomy, but USS was not. This study casts doubt over previous evidence that an elevated serum bilirubin is a specific marker for appendiceal perforation. Instead, we propose that it has utility in diagnosing acute appendicitis, irrespective of whether perforation has occurred. This study also questions the practice of using abdominal USS to investigate for acute appendicitis. Our results showed that USS did not reduce the rate of negative appendicectomy and did not improve the accuracy of diagnosis. Therefore, we suggest CT scanning should be considered the first line imaging modality for investigation of acute appendicitis if diagnosis is in doubt. Although acute appendicitis remains a clinical diagnosis, it should be borne in mind that additional diagnostic tests are available. We submit that these should be used where there is diagnostic uncertainty following consideration of the risks and benefits of further investigation before taking a patient to theatre. Ethical approval None.
Sources of funding None. Author contribution MA Abdelhalim e data collection, data analysis, writing of manuscript. JDA Stuart e data collection, data analysis, review of manuscript. GA Nicholson e original idea, supervised data collection and analysis, review and correction of manuscript. Conflict of interest statement None. Guarantor MA Abdelhalim. References [1] P.H. Smith, The diagnosis of appendicitis;, Postgrad. Med. J. 41 (1965) 2e5. [2] M. Sand, F.G. Bechara, T. Holland-Letz, et al., Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis, Am. J. Surg. 198 (2009) 193e198. [3] A. Emmanuel, P. Murchan, I. Wilson, et al., The value of hyperbilirubinaemia in the diagnosis of acute appendicitis;, Ann. R. Coll. Surg. Engl. 93 (2011) 213e217. €a €kko € nen, P. Salminen, et al., Elevated serum bilirubin in [4] S. Giordano, M. Pa assessing the likelihood of perforation in acute appendicitis: a diagnostic meta-analysis, Int. J. Surg. 11 (2013) 795e800. [5] Y.A. Al-Abed, N. Alobaid, F. Myint, Diagnostic markers in acute appendicitis, Am. J. Surg. (2014 July 29), http://dx.doi.org/10.1016/j.amjsurg.2014.05.024 ([Epub ahead of print]). [6] P. Chaudhary, A. Kumar, N. Sexena, U.C. Biswal, Hyperbilirubinemia as a predictor of gangrenous/perforated appendicitis: a prospective study, Ann. Gastroenterol. 26 (4) (2013) 325e331. [7] S.A. Seetahal, O.B. Bolorunduro, T.C. Sookdeo, et al., Negative appendectomy: a 10-year review of a nationally representative sample, Am. J. Surg. 201 (4) (2011) 433e437. [8] C. McBurney, The incision made in the abdominal wall in cases of appendicitis, with a description of a new method of operating;, Ann. Surg. 20 (1) (1894) 38e43. [9] H. Masoomi, N.T. Nguyen, M.O. Dolich, et al., Laparoscopic appendectomy trends and outcomes in the United States: data from the Nationwide Inpatient Sample (NIS), 2004-2011, Am. Surg. 80 (10) (2014) 1074e1077. [10] S. Olmi, S. Magnone, A. Bertolini, et al., Laparoscopic versus open appendectomy in acute appendicitis: a randomized prospective study, Surg. Endosc. 19 (9) (2005) 1193e1195. [11] J.E. Thomson, D. Kruger, C. Jann-Kruger, et al., Laparoscopic versus open surgery for complicated appendicitis: a randomized controlled trial to prove safety, Surg. Endosc. (2014), http://dx.doi.org/10.1007/s00464-014-3906-y. Oct 16 [Epub ahead of print]. [12] N.T. Ward, S.L. Ramamoorthy, D.C. Chang, et al., Laparoscopic appendectomy is safer than open appendectomy in an elderly population, JSLS. 18 (3) (2014). [13] R.E. Andersson, Short-term complications and long-term morbidity of laparoscopic and open appendicectomy in a national cohort, Br. J. Surg. 101 (9) (2014) 1135e1142. [14] A. Casarotto, F.R. Zarantonello, M. Rebonato, Appendectomy in women. Is the laparoscopic approach always better than the “open” approach in uncomplicated appendicitis? Surg. Laparosc. Endosc. Percutan. Tech. 24 (5) (2014) 406e409. [15] SPSS© 22.0 for Windows©, SPSS Inc., Chicago, IL. [16] I. Zoarets, N. Poluksht, A. Halevy, Does selective use of computed tomography
M.A. Abdelhalim et al. / International Journal of Surgery 17 (2015) 5e9 scan reduce the rate of “white” (negative) appendectomy? Isr. Med. Assoc. J. 16 (6) (2014) 335e337. [17] J.H. Park, LOCAT Group; diagnostic imaging utilization in cases of acute appendicitis: multi-center experience, J. Korean Med. Sci. 29 (9) (2014) 1308e1316. [18] S. Kiatpongsan, L. Meng, J.D. Eisenberg, et al., Imaging for appendicitis: should radiation-induced Cancer risks affect modality selection? Radiology. 273 (2) (2014) 472e482. [19] M.T. Corwin, M. Chang, G. Fananapazir, et al., Accuracy and radiation dose
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reduction of a limited abdominopelvic CT in the diagnosis of acute appendicitis, Abdom. Imaging. (2014), http://dx.doi.org/10.1007/s00261-014-0280-0. Oct 21 [Epub ahead of print]. [20] A.L. Hryhorczuk, R.C. Mannix, G.A. Taylor, Pediatric abdominal pain: use of imaging in the emergency department in the United States from 1999 to 2007, Radiology. 263 (3) (2012) 778e785. [21] D. Owens, J. Evans, Population studies on Gilbert's syndrome, J. Med. Genet. 12 (2) (1975) 152e156.
Contents lists available at ScienceDirect
International Journal of Surgery journal homepage: www.journal-surgery.net
Original research
Augmenting the decision making process in acute appendicitis: A retrospective cohort study M.A. Abdelhalim a, b, *, J.D.A. Stuart a, b, G.A. Nicholson a, b a b
Western Infirmary Glasgow, NHS Greater Glasgow & Clyde, UK University of Glasgow, Glasgow, UK
h i g h l i g h t s Pre-operative investigation in acute appendicitis is analysed. Elevated WCC and CRP are sensitive but non-specific markers in acute appendicitis. Elevated serum bilirubin is a specific but insensitive marker in acute appendicitis. CT scanning reduces negative appendicectomy rate to 1%. Ultrasound scanning does not reduce negative appendicectomy rate.
a r t i c l e i n f o
a b s t r a c t
Article history: Received 4 December 2014 Received in revised form 23 February 2015 Accepted 5 March 2015 Available online 14 March 2015
Introduction: Acute appendicitis is a common surgical diagnosis. We investigated the use of blood markers (WCC, CRP and serum bilirubin) and diagnostic imaging (USS and CT scan) to arrive at this diagnosis, as well as the surgical approach used for appendicectomy. Methods: This was a retrospective analysis of consecutive patients undergoing appendicectomy in seven hospitals within GG&C Health Board during a 6 month study period. Data were collected from electronic patient records. Sensitivity and specificity of each investigation for diagnosing acute appendicitis was calculated. Results: 363 patients were included. Appendicectomy was performed open in 53%, laparoscopically in 43% and converted in 4%. Diagnostic imaging was used in 38%. The overall negative appendicectomy rate was 15% (18% when no imaging was used, 23% when USS was used and 1% when CT scanning was used). Elevated bilirubin had a sensitivity of 0.44 and a specificity of 0.84 for detecting acute appendicitis. Sensitivity and specificity for elevated WCC were 0.78 and 0.55, and for elevated CRP were 0.81 and 0.59, respectively. The specificity of bilirubin for diagnosing perforated appendicitis was 0.63. Discussion: WCC and CRP were sensitive blood markers in acute appendicitis, whereas serum bilirubin was more specific. Diagnostic imaging with a CT scan was very effective at reducing the rate of negative appendicectomy, but USS was not. Conclusion: Serum bilirubin has utility in diagnosing acute appendicitis, irrespective of whether perforation has occurred. CT scanning should be considered the first line imaging modality for investigation of acute appendicitis if diagnosis is in doubt. © 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
Keywords: Appendicitis Appendicectomy Appendectomy Diagnosis Bilirubin Hyperbilirubinaemia CRP White cell count CT scan Ultrasound scan Laparoscopic
1. Introduction Acute appendicitis is a common surgical emergency. However, the differential diagnosis is wide, especially in females. Mesenteric adenitis, ovarian pathologies, mittelschmerz, pelvic inflammatory
* Corresponding author. Western Infirmary Glasgow, Dumbarton Road, G11 6NT Glasgow, UK. http://dx.doi.org/10.1016/j.ijsu.2015.03.004 1743-9191/© 2015 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
disease and inflammatory bowel disease are all possible causes of right iliac fossa pain. This diagnostic conundrum has been appreciated for many years. Additional biochemical investigations have long been used to compliment the clinical diagnosis [1]. The main investigations in current use are blood inflammatory markers, namely white cell count (WCC) and C-reactive protein (CRP), as well as the imaging modalities of abdominal ultrasound scan (USS) and computed tomography (CT) scan. More recently, serum
6
M.A. Abdelhalim et al. / International Journal of Surgery 17 (2015) 5e9
bilirubin has been shown to be a more specific marker for acute appendicitis, especially when perforation is more likely [2e5]. The pathophysiology of this bilirubin rise is unclear. It may be that with inflammation and infection of the appendix, especially if there is perforation, bacteria are allowed to enter the portal circulation. These bacteria would then arrive at the liver and if the load is high enough to overwhelm the Kupffer cell function of the liver, a degree of hepatocyte damage may occur, which would be reflected as a rise in serum bilirubin [6]. A negative appendicectomy has the drawbacks of exposing the patient to unnecessary surgery and delaying the definitive diagnosis, as well as incurring unnecessary financial cost. The overall rate of negative appendicectomy is reducing. This could be attributed to better diagnostics [7]. It does however remain a common problem that general surgeons strive to avoid. Any appropriate test that can increase the accuracy of diagnosis is therefore valuable. The open appendicectomy for treatment of acute appendicitis is an old operation, with the popular McBurney incision being described in 1894 [8]. Although the open approach remains entirely valid, there has been a recent move to the more modern laparoscopic approach, especially in women [9]. There are conflicting opinions about whether open or laparoscopic appendicectomy should be favoured routinely and it seems that both approaches are equally safe and effective in experienced hands [10e14]. The study aims to examine the current utilisation of preoperative investigations to diagnose acute appendicitis. The value of the blood markers WCC, CRP and serum bilirubin as well as the imaging modalities of abdominal USS and CT scan in diagnosing acute appendicitis and avoiding negative appendicectomy will be investigated.
2. Methods This was a retrospective analysis of 500 consecutive patients undergoing appendicectomy in seven hospitals within the Greater Glasgow & Clyde Health Board from 19/09/2012 to 05/03/2013. Data were collected from the electronic patient records through the health board Clinical Portal system. Inclusion criteria were then applied to select the appropriate patient group (Fig. 1). Baseline demographics were recorded for each patient including age, sex, date of operation and hospital. Blood results were reviewed. The white cell count (WCC), C-reactive protein (CRP) and serum bilirubin results on admission were noted. According to local laboratory reference ranges, elevated WCC was taken to be greater than 10.0 109/L. Elevated CRP was greater than 10 mg/L and elevated serum bilirubin was greater than 20 mmol/L. Radiology reports were examined to investigate the use of imaging in the diagnosis of acute appendicitis. Pathology reports were also read to ascertain the final diagnosis. This was recorded as normal appendix, simple acute appendicitis, or acute appendicitis with perforation. The operative approach was obtained from examination of the operative notes. Biochemical, histopathological and radiological variables were correlated and statistical analysis was then performed using SPSS
version 22 [15]. Clinical details on admission were not collected or used in the analysis. However, at the time of operation, all patients in this study had a clinical diagnosis of acute appendicitis. Baseline blood tests were performed in all patients on admission. There is no institutional policy on the use of imaging for acute appendicitis and therefore, when imaging was used, it was due to uncertainty over the diagnosis.
3. Results The patient records of 500 consecutive patients undergoing appendicectomy for suspected acute appendicitis in the Greater Glasgow & Clyde Health Board between 19/09/12 and 05/03/2013 were examined. The inclusion criteria were met by 363 patients, who were included in the analysis (Fig. 1). Of these patients, 226 (62%) were male and 137 (38%) were female. The age range was 3e86 years. Mean age was 31 years. Pre-operative diagnostic imaging was utilised in 137 (38%) patients. An USS only was performed in 58 (16%) patients and a CT scan only was performed in 71 (20%) patients. Eight patients (2%) were imaged with both USS and CT scan. Of the female patients, 53% had pre-operative diagnostic imaging, compared to only 28% of male patients (p < 0.005). There was also a gender difference in the chosen modality of imaging, with a CT scan being performed in 72% of males imaged compared to 40% of females imaged, where ultrasound scan was favoured (Table 1). The negative appendicectomy rate in patients who did not have any pre-operative imaging was 18%, compared to 23% in patients who had an USS and 1% in those who had a CT scan (Table 2). Statistical analysis showed that performance of a CT scan significantly increased the accuracy of diagnosis (p < 0.005), whereas USS did not. Operative data were available for 306 patients in the study. Of these patients, 162 (53%) had an open appendicectomy and 132 (43%) had a laparoscopic appendicectomy. The remaining 12 (4%) patients had the procedure started laparoscopically, then converted to open. A laparoscopic approach was favoured in females and was attempted first in 74%. This compares to only 31% of males, creating a significant gender difference in the choice of approach (p < 0.005). Table 3 illustrates the operative approach used by gender. Pathology results were reviewed for all 363 patients in the study. In 56 (15%) cases, the appendix was found to be normal. Appendicitis without perforation was diagnosed in 254 (70%) cases and perforated appendicitis was found in 53 (15%) patients. Bilirubin, WCC and CRP levels were compared to pathology, as summarised in (Table 4). There was a significant rise in all three blood markers in patients with acute appendicitis (p < 0.005). There was also a significant difference in the levels of all blood markers between those with simple appendicitis and those with perforated appendicitis (p < 0.005). When a standard laboratory reference range was used, an elevated bilirubin had a sensitivity of 0.44 and a specificity of 0.84 for detecting acute appendicitis. Meanwhile, an elevated WCC had a sensitivity of 0.78 and specificity of 0.55. Elevated CRP had a sensitivity of 0.81 and specificity of 0.59. Positive predictive value and negative predictive value were also calculated for each of the
Table 1 Pre-operative diagnostic imaging and gender.
Fig. 1. Inclusion criteria.
Male Female
Ultrasound scan
CT scan
No imaging
19 (8%) 47 (34%)
48 (21%) 31 (23%)
162 (72%) 64 (47%)
M.A. Abdelhalim et al. / International Journal of Surgery 17 (2015) 5e9 Table 2 Pre-operative diagnostic imaging and negative appendicectomy rate.
Normal Appendix Acute Appendicitis
Ultrasound scan
CT scan
No imaging
15 (23%) 51 (77%)
1 (1%) 78 (99%)
40 (18%) 186 (82%)
Table 3 Operative approach and gender.
Male Female
Open
Laparoscopic
Conversion
132 (69%) 30 (26%)
53 (28%) 79 (69%)
7 (3%) 5 (5%)
Table 4 Blood markers and pathology.
Elevated Bilirubina Elevated WCCa Elevated CRPa
Normal appendix (n ¼ 56)
Appendicitis without perforation (n ¼ 254)
Perforated appendicitis (n ¼ 53)
9 25 23
106 192 201
28 48 49
a According to local laboratory reference ranges, elevated WCC 10.0 109/L, elevated CRP 10 mg/L, and elevated serum bilirubin 20 mmol/L.
blood markers. Bilirubin had the highest PPV while CRP had the highest NPV (Table 5). The same analysis was performed separately for the subgroup of patients who did not undergo diagnostic imaging in order to assess the utility of these blood markers in the absence of imaging. There was no significant difference in the sensitivity, specificity, PPV or NPV of any of these blood markers for detecting acute appendicitis in this patient group (Table 6). When only cases of perforated appendicitis were considered, an elevated bilirubin had a sensitivity of 0.53 and specificity of 0.63; PPV was 0.20 and NPV was 0.63. By comparison, elevated WCC had a sensitivity of 0.91 and specificity of 0.30, while elevated CRP had a sensitivity of 0.92 and specificity of 0.28. 4. Discussion Acute appendicitis is a common surgical diagnosis. We investigated the use of blood markers and diagnostic imaging to arrive at this diagnosis, as well as the surgical approach used for appendicectomy in our large population.
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rate to 1% when patients were imaged by CT scan. USS did not improve diagnostic accuracy. These figures are comparable to a study by Zoarets et al. who demonstrated a negative appendicectomy rate of 18.8% with a CT utilisation rate of 35.2% [16]. This diagnostic approach illustrated by the current study is in contrast to the centres in Seoul, Korea, where imaging utilisation rate was 99.7% and overall negative appendicectomy rate was 4.1% [17]. It is evident that increasing use of imaging, particularly CT scanning, can improve diagnostic accuracy and reduce the rate of negative appendicectomy. This has to be balanced with the well documented radiation risks of imaging and decisions should be made after considering both the risks and the benefits [18]. Perhaps limited range CT scanning can be used to limit radiation exposure yet maintain diagnostic accuracy [19]. Pre-operative diagnostic imaging was almost twice as likely to be utilised in female patients than in males in the current study. This is perhaps due to the greater diagnostic uncertainty in females with right iliac fossa pain such as the possibility of ovarian pathology. Female patients were more likely to be imaged with USS while CT scanning was more widely utilised in males. Similar findings have previously been documented [20]. This may be due to a greater caution taken with radiation risk in young females. 4.2. Approach Laparoscopic appendicectomy was the operation of choice in 47% of patients in our study group. In 4% of patients, the operation was converted to an open procedure and so the rate of completed laparoscopic appendicectomy was 43%. In many centres there is a general trend towards a laparoscopic approach for appendicectomy [9]. Extensive evidence is available to support the safety of laparoscopic appendicectomy for both simple and complicated appendicitis [10e12]. Other studies have highlighted the added cost of laparoscopic appendicectomy for little or no added benefit [14]. Ultimately, the choice of surgical approach depends on the local institution, the surgeon's experience and patient preference [13]. The current data show a significant difference in operative approach between genders with laparoscopy being chosen in 74% of females compared to only 31% of males (Table 3). The reasons behind this difference were not investigated in the study. However, it may be that the greater diagnostic uncertainty in females leads surgeons to favour diagnostic laparoscopy, which then proceeds to laparoscopic appendicectomy in some cases. It is also possible that the scar of an open appendicectomy is less acceptable in female patients than in males. 4.3. Blood markers
4.1. Diagnostic imaging Despite modern imaging techniques, appendicitis remains a clinical diagnosis in the first instance. Other tests are used as adjuncts. This is highlighted by the finding that the majority of patients in the study group (62%) proceeded to surgery without any diagnostic imaging. However, the current data show that the negative appendicectomy rate in patients who did not undergo diagnostic imaging is 18%. There was a significant reduction in this
The levels of WCC, CRP and bilirubin were all associated significantly with degree of inflammation in appendicitis. A rise in all blood markers was seen in simple appendicitis, and a greater rise was seen in perforated appendicitis. The use of WCC and CRP as inflammatory markers is long standing and although sensitive, these markers are not specific for acute appendicitis. Recently, a wealth of evidence has accumulated for the use of serum bilirubin as a specific marker in acute appendicitis and especially perforated
Table 5 Sensitivity and specificity of blood markers for detecting acute appendicitis.
Elevated Bilirubina Elevated WCCa Elevated CRPa a
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
0.44 (0.38e0.49) 0.78 (0.73e0.83) 0.81 (0.77e0.86)
0.84 (0.71e0.92) 0.55 (0.42e0.68) 0.59 (0.45e0.72)
0.94 (0.88e0.97) 0.91 (0.86e0.94) 0.92 (0.87e0.94)
0.21 (0.16e0.27) 0.32 (0.23e0.42) 0.37 (0.27e0.48)
According to local laboratory reference ranges, elevated WCC 10.0 109/L, elevated CRP 10 mg/L, and elevated serum bilirubin 20 mmol/L.
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M.A. Abdelhalim et al. / International Journal of Surgery 17 (2015) 5e9
Table 6 Sensitivity and specificity of blood markers for detecting acute appendicitis in patients who did not undergo diagnostic imaging.
Elevated Bilirubina Elevated WCCa Elevated CRPa a
Sensitivity (95% CI)
Specificity (95% CI)
PPV (95% CI)
NPV (95% CI)
0.42 (0.35e0.49) 0.81 (0.74e0.86) 0.80 (0.73e0.85)
0.83 (0.67e0.92) 0.55 (0.39e0.70) 0.60 (0.43e0.75)
0.92 (0.83e0.96) 0.89 (0.83e0.93) 0.90 (0.84e0.94)
0.23 (0.17e0.31) 0.38 (0.26e0.52) 0.39 (0.27e0.53)
According to local laboratory reference ranges, elevated WCC 10.0 109/L, elevated CRP 10 mg/L, and elevated serum bilirubin 20 mmol/L.
appendicitis [2e5]. The current study demonstrated that an elevated bilirubin has a specificity of 0.84 and positive predictive value of 0.94 for acute appendicitis, higher than both WCC and CRP. However, its sensitivity was low at only 0.44 (Table 5). When only cases of perforated appendicitis were considered, it was found that the specificity of an elevated bilirubin was only 0.63 and the PPV was 0.20. These results are in contrast to previous studies which advocated the use of serum bilirubin to detect acute appendicitis with perforation [2,4]. The results of the current study support the use of bilirubin as a novel diagnostic marker in cases of suspected acute appendicitis, and if noted to be high in these cases suspicion should certainly be raised. It should be used with caution however, as our data suggest that serum bilirubin may be normal in over half of cases of acute appendicitis. At best, serum bilirubin is a useful adjunctive diagnostic marker. In detecting cases where perforation had occurred, we found that serum bilirubin was a poor predictive marker and therefore we would not recommend its use in identifying these cases. Gilbert's syndrome is a genetic liver disorder affecting up to 6% of the population that causes a rise in serum bilirubin [21]. No effort was made to trace and exclude these patients from the study. However, given the number of patients in the study, it is unlikely that this confounding factor would affect the overall conclusions. 5. Conclusion In this retrospective study we investigated the use of preoperative blood markers and imaging in aiding the diagnosis of acute appendicitis. We also examined the surgical approach to appendicectomy in our region. WCC and CRP were sensitive blood markers, whereas serum bilirubin was the most specific blood marker in acute appendicitis. Diagnostic imaging with a CT scan was very effective at reducing the rate of negative appendicectomy, but USS was not. This study casts doubt over previous evidence that an elevated serum bilirubin is a specific marker for appendiceal perforation. Instead, we propose that it has utility in diagnosing acute appendicitis, irrespective of whether perforation has occurred. This study also questions the practice of using abdominal USS to investigate for acute appendicitis. Our results showed that USS did not reduce the rate of negative appendicectomy and did not improve the accuracy of diagnosis. Therefore, we suggest CT scanning should be considered the first line imaging modality for investigation of acute appendicitis if diagnosis is in doubt. Although acute appendicitis remains a clinical diagnosis, it should be borne in mind that additional diagnostic tests are available. We submit that these should be used where there is diagnostic uncertainty following consideration of the risks and benefits of further investigation before taking a patient to theatre. Ethical approval None.
Sources of funding None. Author contribution MA Abdelhalim e data collection, data analysis, writing of manuscript. JDA Stuart e data collection, data analysis, review of manuscript. GA Nicholson e original idea, supervised data collection and analysis, review and correction of manuscript. Conflict of interest statement None. Guarantor MA Abdelhalim. References [1] P.H. Smith, The diagnosis of appendicitis;, Postgrad. Med. J. 41 (1965) 2e5. [2] M. Sand, F.G. Bechara, T. Holland-Letz, et al., Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis, Am. J. Surg. 198 (2009) 193e198. [3] A. Emmanuel, P. Murchan, I. Wilson, et al., The value of hyperbilirubinaemia in the diagnosis of acute appendicitis;, Ann. R. Coll. Surg. Engl. 93 (2011) 213e217. €a €kko € nen, P. Salminen, et al., Elevated serum bilirubin in [4] S. Giordano, M. Pa assessing the likelihood of perforation in acute appendicitis: a diagnostic meta-analysis, Int. J. Surg. 11 (2013) 795e800. [5] Y.A. Al-Abed, N. Alobaid, F. Myint, Diagnostic markers in acute appendicitis, Am. J. Surg. (2014 July 29), http://dx.doi.org/10.1016/j.amjsurg.2014.05.024 ([Epub ahead of print]). [6] P. Chaudhary, A. Kumar, N. Sexena, U.C. Biswal, Hyperbilirubinemia as a predictor of gangrenous/perforated appendicitis: a prospective study, Ann. Gastroenterol. 26 (4) (2013) 325e331. [7] S.A. Seetahal, O.B. Bolorunduro, T.C. Sookdeo, et al., Negative appendectomy: a 10-year review of a nationally representative sample, Am. J. Surg. 201 (4) (2011) 433e437. [8] C. McBurney, The incision made in the abdominal wall in cases of appendicitis, with a description of a new method of operating;, Ann. Surg. 20 (1) (1894) 38e43. [9] H. Masoomi, N.T. Nguyen, M.O. Dolich, et al., Laparoscopic appendectomy trends and outcomes in the United States: data from the Nationwide Inpatient Sample (NIS), 2004-2011, Am. Surg. 80 (10) (2014) 1074e1077. [10] S. Olmi, S. Magnone, A. Bertolini, et al., Laparoscopic versus open appendectomy in acute appendicitis: a randomized prospective study, Surg. Endosc. 19 (9) (2005) 1193e1195. [11] J.E. Thomson, D. Kruger, C. Jann-Kruger, et al., Laparoscopic versus open surgery for complicated appendicitis: a randomized controlled trial to prove safety, Surg. Endosc. (2014), http://dx.doi.org/10.1007/s00464-014-3906-y. Oct 16 [Epub ahead of print]. [12] N.T. Ward, S.L. Ramamoorthy, D.C. Chang, et al., Laparoscopic appendectomy is safer than open appendectomy in an elderly population, JSLS. 18 (3) (2014). [13] R.E. Andersson, Short-term complications and long-term morbidity of laparoscopic and open appendicectomy in a national cohort, Br. J. Surg. 101 (9) (2014) 1135e1142. [14] A. Casarotto, F.R. Zarantonello, M. Rebonato, Appendectomy in women. Is the laparoscopic approach always better than the “open” approach in uncomplicated appendicitis? Surg. Laparosc. Endosc. Percutan. Tech. 24 (5) (2014) 406e409. [15] SPSS© 22.0 for Windows©, SPSS Inc., Chicago, IL. [16] I. Zoarets, N. Poluksht, A. Halevy, Does selective use of computed tomography
M.A. Abdelhalim et al. / International Journal of Surgery 17 (2015) 5e9 scan reduce the rate of “white” (negative) appendectomy? Isr. Med. Assoc. J. 16 (6) (2014) 335e337. [17] J.H. Park, LOCAT Group; diagnostic imaging utilization in cases of acute appendicitis: multi-center experience, J. Korean Med. Sci. 29 (9) (2014) 1308e1316. [18] S. Kiatpongsan, L. Meng, J.D. Eisenberg, et al., Imaging for appendicitis: should radiation-induced Cancer risks affect modality selection? Radiology. 273 (2) (2014) 472e482. [19] M.T. Corwin, M. Chang, G. Fananapazir, et al., Accuracy and radiation dose
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