ORIGINAL ARTICLE ANZJSurg.com
Hyperbilirubinaemia: its utility in non-perforated appendicitis Anna Sandstrom and David A. Grieve Department of Surgery, Nambour General Hospital, Nambour, Queensland, Australia
Key words appendicitis, bilirubin, biological markers, diagnosis, leukocyte count. Correspondence Dr Anna Sandstrom, Department of Surgery, Nambour General Hospital, Hospital Road, Nambour, QLD 4560, Australia. Email: [email protected] A. Sandstrom MBBS, BSc; D. A. Grieve MBBS, MMed, FRACS, FACS. This study was presented at the 2015 Annual Scientific Congress in Perth. Accepted for publication 23 September 2015. doi: 10.1111/ans.13373
Abstract Background: The diagnosis of acute appendicitis is made using clinical findings and investigations. Recent studies have suggested that serum bilirubin, a cheap and simple biochemical test, is a positive predictor in the diagnosis of appendiceal perforation and may be more specific than C-reactive protein (CRP) and white cell count (WCC). The aim of this study was to investigate the utility of the serum bilirubin level in patients with suspected acute but non-perforative appendicitis. Methods: A retrospective chart review of 213 patients who presented with suspected appendicitis in a 6-month period to Nambour General Hospital was performed. Serum bilirubin, WCC and CRP were recorded and analysed as to their utility in relation to the final diagnosis. Results: A total of 196 patients underwent an appendicectomy and 41 of these were negative. The specificity of hyperbilirubinaemia for appendicitis overall was 0.83 with a positive predictive value (PPV) of 0.86, compared with CRP (specificity 0.40, PPV 0.75) and WCC (specificity 0.67, PPV 0.85). The area under the receiver operating characteristic curve for bilirubin was 0.6289 compared to 0.6171 for CRP and 0.7219 for WCC. A subgroup analysis of those with complicated appendicitis demonstrated a PPV for bilirubin of 0.66 compared to 0.58 for WCC and 0.34 for CRP in agreement with the literature. Subgroup analysis of hyperbilirubinaemia in simple appendicitis demonstrated a PPV of 0.81 compared to CRP (0.71) and WCC (0.82). Conclusion: Bilirubin had a higher specificity than CRP and WCC overall in patients with appendicitis. Hyperbilirubinaemia had a high PPV in patients with simple appendicitis.
Introduction Acute appendicitis is one of the most commonly encountered surgical conditions with the lifetime risk of having appendicitis estimated at 7%.1,2 Simple acute appendicitis has a low mortality rate of 0.3% but increases to 5–6% when combined with factors such as extremes of age, pre-existing comorbidities and appendix perforation.2 Local and systemic complications such as abdominal abscess formation, sepsis, peritonitis and small bowel obstruction can occur with delayed diagnosis and treatment of a perforated appendix.3 The diagnosis of appendicitis is made on clinical grounds in conjunction with imaging and blood investigations. There is no single clinical test or investigation that can reliably predict appendicitis. The diagnosis of appendicitis can be problematic in those who present with atypical symptoms (20–33%) and there is generally a low threshold for a diagnostic laparoscopy.4 The rate of negative appendicectomy has been estimated at 10–30% and is highest in females of reproductive age (28.7%).5–7 These figures suggest that © 2015 Royal Australasian College of Surgeons
there is room for improvement in the diagnosis of appendicitis to reduce the rate of unnecessary surgery and decrease costs to the health care system. There have been some recent studies that suggest that bilirubin, a cheap and simple biochemical test, is a positive predictor for appendiceal perforation and may be more specific than C-reactive protein (CRP) and white cell count (WCC) in diagnosis of acute appendicitis.6,8–13 The aim of this study was to investigate the usefulness of bilirubin in the diagnosis of appendicitis and to assess its utility in differentiating simple versus complicated appendicitis.
Materials and methods A retrospective chart review was performed on all patients admitted to Nambour General Hospital with suspected appendicitis over a 6-month period from October 2013 to April 2014. Data were collected on patient demographics, results for serological tests taken ANZ J Surg •• (2015) ••–••
2
Sandstrom and Grieve
0.41 0.67 0.80
0.83 0.67 0.40
0.86 0.85 0.75
Table 2 Values of bilirubin, white cell count (WCC) and C-reactive protein (CRP) for differentiating simple appendicitis from non-appendicitis
Bilirubin (n = 184) WCC (n = 181) CRP (n = 72)
Sensitivity
Specificity
Positive predictive value
0.35 0.63 0.77
0.83 0.67 0.40
0.81 0.82 0.71
on admission (liver function tests, WCC, CRP) and histological results. A total of 250 patients were admitted with suspected appendicitis. Two hundred and thirteen patients were included in the study and 37 patients were excluded from the study. Patients were excluded from the study if they did not have liver function tests performed on admission (36 patients), if they were known to have persistently deranged liver function tests or if they had history of known liver disease (one patient). Patients were first divided into two groups according to histology: appendicitis versus no appendicitis. Patients that were discharged without an operation (17) were included in the no appendicitis group. The appendicitis group was then further broken down into simple (acute) appendicitis and complicated (gangrenous/ perforated) appendicitis. Sensitivities, specificities and positive predictive values for total bilirubin, WCC and CRP were calculated for these groups. Additionally, receiver operating characteristic (ROC) curve analysis was performed for bilirubin, WCC and CRP. Hyperbilirubinaemia was defined as a total serum bilirubin level of ≥20 μmol/L, a raised WCC of ≥11 × 109 and a raised CRP as ≥5 mg/L. Statistical analysis was performed using Stata 12 (StataCorp. 2011. Stata Statistical Software: Release 12. StataCorp LP., College Station, TX, USA).
Results The results are presented in Tables 1–4 and Figures 1–3.
Discussion Hyperbilirubinaemia is caused by an increased production or a reduced clearance of bilirubin.6 Bacterial infections, especially those caused by gram-negative pathogens, affect bile production and flow.14 Escherichia coli is the most common organism isolated from peritoneal fluid and through inflammation and subsequent ulceration of the appendix, bacteria can enter the portal circulation.6,8,14,15 Hyperbilirubinaemia in appendicitis is thought to occur through
Bilirubin (n = 87) WCC (n = 84) CRP (n = 33)
Sensitivity
Specificity
Positive predictive value
0.66 0.86 1.00
0.83 0.67 0.40
0.66 0.58 0.34
Table 4 Values of bilirubin, white cell count (WCC) and C-reactive protein (CRP) for differentiating complicated appendicitis from simple appendicitis Sensitivity
Specificity
Positive predictive value
0.65 0.86 1.00
0.65 0.37 0.23
0.30 0.24 0.40
Bilirubin (n = 155) WCC (n = 155) CRP (n = 55)
1.00
Positive predictive value
Sensitivity 0.50 0.75
Specificity
0.25
Bilirubin (n = 213) WCC (n = 210) CRP (n = 80)
Sensitivity
Table 3 Values of bilirubin, white cell count (WCC) and C-reactive protein (CRP) for differentiating complicated appendicitis from non-appendicitis
0.00
Table 1 Values of bilirubin, white cell count (WCC) and C-reactive protein (CRP) for differentiating appendicitis from non-appendicitis
0.00
0.25
0.50 1 - Specificity
0.75
1.00
Area under ROC curve = 0.6289
Fig. 1. Bilirubin: receiver operating characteristic (ROC) curve for total cohort of appendicitis patients.
several underlying mechanisms including intravascular hemolysis and endotoxaemia.8 Lipopolysaccharides associated with E. coli have been shown in vivo to cause cholestasis by affecting hepatocyte uptake and bile acid secretion.6 This endotoxin-induced cholestasis has also been associated with general gastrointestinal perforation and bilirubin increases with severity of intra-abdominal infection.9 Given this relationship between bilirubin and severity, it is hypothesized that bilirubin levels can be used to determine the likelihood of appendiceal perforation. Several studies have reported a relationship between appendiceal perforation and hyperbilirubinaemia. Estrada et al.,10 Hong et al.11 and Sand et al.12 found that patients with perforation or gangrene were significantly more likely to have hyperbilirubinaemia than those with simple acute appendicitis and the risk of appendiceal perforation was three times higher for patients with hyperbilirubinaemia than those with normal serum bilirubin levels. Bilirubin has also been identified as having a higher specificity but lower sensitivity than CRP for appendiceal perforation. Burcharth © 2015 Royal Australasian College of Surgeons
3
0.00
0.25
Sensitivity 0.50 0.75
1.00
Hyperbilirubinaemia in appendicitis
0.00
0.25
0.50 1 - Specificity
0.75
1.00
Area under ROC curve = 0.6171
0.00
0.25
Sensitivity 0.50 0.75
1.00
Fig. 2. C-reactive protein: receiver operating characteristic (ROC) curve for total cohort of appendicitis patients.
found that the odds ratio of having appendicitis in the context of elevated bilirubin on admission was 3.25. They also found hyperbilirubinaemia had a specificity of 0.88 for acute appendicitis and the positive predictive value was 0.91. Emmanuel reported bilirubin to be more specific than CRP for both simple appendicitis and perforated or gangrenous appendicitis. The role of bilirubin in the diagnosis of appendicitis has not been widely researched and the majority of the studies have focussed on hyperbilirubinaemia in perforated appendicitis. This study found that hyperbilirubinaemia had a higher specificity (0.83) for distinguishing between patients with simple appendicitis and patients without appendicitis than WCC and CRP (0.67 and 0.40, respectively). Hyperbilirubinaemia had a higher PPV (0.86) for appendicitis than WCC and CRP (0.85 and 0.75, respectively). In a subgroup analysis of patients with simple appendicitis, hyperbilirubinaemia had a higher PPV than CRP (0.81 versus 0.71) and a similar PPV to WCC (0.82). When distinguishing those patients with complicated appendicitis from those with simple appendicitis, hyperbilirubinaemia had a higher specificity (0.65) compared to WCC and CRP (0.37 and 0.23, respectively). The ROC curve for the total cohort demonstrated that bilirubin was at least as good as CRP as a diagnostic test for appendicitis (area under the ROC curve 0.6289 versus 0.6171) though not as good as WCC (area under the ROC curve 0.7219). This study is limited by its retrospective design making it difficult to reliably exclude pre-existing liver disease. There were a limited number of patients with CRP levels measured on admission which may reflect a clinical bias of severity. Additionally, patients discharged without an operation were included in the non-appendicitis group; however, presentation at another hospital with subsequent appendicectomy could not be excluded.
0.00
0.25
0.50 1 - Specificity
0.75
1.00
Area under ROC curve = 0.7219
Fig. 3. White cell count: receiver operating characteristic (ROC) curve for total cohort of appendicitis patients.
et al. found that elevated total bilirubin levels had a low sensitivity (0.38–0.77) but high specificity (0.70–0.87) for identifying perforated appendicitis while CRP had a higher sensitivity but lower specificity in the same population. Sand et al.12 similarly reported a specificity of 0.86 for bilirubin in perforated appendicitis compared with WCC (0.55) and CRP (0.39). Again, CRP and WCC were more sensitive (0.81 and 0.96, respectively) than bilirubin (0.7). A large study by Giardano et al.13 found that hyperbilirubinaemia had a sensitivity of 0.49 and specificity of 0.82 with an odds ratio of 4.42 for predicting perforation in appendicitis. McGowan et al.16 looked at 1271 patients with appendicitis and reported that CRP and bilirubin were significantly higher in patients with appendiceal perforation with CRP being more sensitive (0.79 versus 0.63) and bilirubin being more specific (0.88 versus 0.63). The above studies only looked at the specificity of bilirubin in appendiceal perforation. A study in Ireland by Emmanuel et al.17 investigated the role of bilirubin in simple appendicitis and © 2015 Royal Australasian College of Surgeons
Conclusion This study highlighted the usefulness of bilirubin in the diagnostic workup of a patient with suspected appendicitis. This study adds to the literature by demonstrating a high PPV for hyperbilirubinaemia in patients with simple appendicitis. Bilirubin is a cheap, readily available biochemical marker that has been shown to be more specific than CRP in patients with appendicitis. In combination with other established clinical, laboratory and radiological tests, adding bilirubin to preliminary investigations could aid in decreasing the rate of negative appendicectomies. This should be further assessed with a prospective study.
References 1. Humes DJ, Simpson J. Acute appendicitis. BMJ 2006; 333: 530–4. 2. Fischer J. Master of Surgery. Philadelphia: Lippincott Williams, 2012. 3. Nomura S, Watanabe M, Komine O et al. Serum total bilirubin elevation is a predictor of the clinicopathological severity of acute appendicitis. Surg. Today 2013; 44: 1104–8. 4. Khairy G. Acute appendicitis: is removal of a normal appendix still existing and can we reduce its rate? Saudi J. Gastroenterol. 2009; 15: 167–70. 5. Jaunoo SS, Hale AL, Masters JP, Jaunoo SR. An international survey of opinion regarding investigation of possible appendicitis and
4
6.
7.
8.
9.
10.
11.
Sandstrom and Grieve
laparoscopic management of a macroscopically normal appendix. Ann. R. Coll. Surg. Engl. 2012; 94: 476–80. Atahan K, Ureyen O, Aslan E et al. Preoperative diagnostic role of hyperbilirubinaemia as a marker of appendix perforation. J. Int. Med. Res. 2011; 39: 609–18. Ma KW, Chia NH, Yeung HW, Cheung MT. If not appendicitis, then what else can it be? A retrospective review of 1492 appendectomies. Hong Kong Med. J. 2010; 16: 12–7. Burcharth J, Pommergaard HC, Rosenberg J, Gogenur I. Hyperbilirubinemia as a predictor for appendiceal perforation: a systematic review. Scand. J. Surg. 2013; 102: 55–60. Hong YR, Chung CW, Kim JW et al. Hyperbilirubinemia is a significant indicator for the severity of acute appendicitis. J. Korean Soc. Coloproctol. 2012; 28: 247–52. Estrada JJ, Petrosyan M, Barnhart J et al. Hyperbilirubinemia in appendicitis: a new predictor of perforation. J. Gastrointest. Surg. 2007; 11: 714–8. Sand M, Bechara FG, Holland-Letz T, Sand D, Mehnert G, Mann B. Diagnostic value of hyperbilirubinemia as a predictive factor for
12.
13.
14. 15.
16.
17.
appendiceal perforation in acute appendicitis. Am. J. Surg. 2009; 198: 193–8. Noh H, Chang SJ, Han A. The diagnostic values of preoperative laboratory markers in children with complicated appendicitis. J. Korean Surg. Soc. 2012; 83: 237–41. Giordano S, Paakkonen M, Salminen P, Gronroos JM. Elevated serum bilirubin in assessing the likelihood of perforation in acute appendicitis: a diagnostic meta-analysis. Int. J. Surg. 2013; 11: 795–800. Miller DF, Irvine RW. Jaundice in acute appendicitis. Lancet 1969; 1: 321–3. Socea B, Carap A, Rac-Albu M, Constantin V. The value of serum bilirubin level and of white blood cell count as severity markers for acute appendicitis. Chirurgia (Bucur) 2013; 108: 829–34. McGowan DR, Sims HM, Shaikh I, Uheba M. The value of hyperbilirubinaemia in the diagnosis of acute appendicitis. Ann. R. Coll. Surg. Engl. 2011; 93: 498. Emmanuel A, Murchan P, Wilson I, Balfe P. The value of hyperbilirubinaemia in the diagnosis of acute appendicitis. Ann. R. Coll. Surg. Engl. 2011; 93: 213–7.
© 2015 Royal Australasian College of Surgeons
Hyperbilirubinaemia: its utility in non-perforated appendicitis Anna Sandstrom and David A. Grieve Department of Surgery, Nambour General Hospital, Nambour, Queensland, Australia
Key words appendicitis, bilirubin, biological markers, diagnosis, leukocyte count. Correspondence Dr Anna Sandstrom, Department of Surgery, Nambour General Hospital, Hospital Road, Nambour, QLD 4560, Australia. Email: [email protected] A. Sandstrom MBBS, BSc; D. A. Grieve MBBS, MMed, FRACS, FACS. This study was presented at the 2015 Annual Scientific Congress in Perth. Accepted for publication 23 September 2015. doi: 10.1111/ans.13373
Abstract Background: The diagnosis of acute appendicitis is made using clinical findings and investigations. Recent studies have suggested that serum bilirubin, a cheap and simple biochemical test, is a positive predictor in the diagnosis of appendiceal perforation and may be more specific than C-reactive protein (CRP) and white cell count (WCC). The aim of this study was to investigate the utility of the serum bilirubin level in patients with suspected acute but non-perforative appendicitis. Methods: A retrospective chart review of 213 patients who presented with suspected appendicitis in a 6-month period to Nambour General Hospital was performed. Serum bilirubin, WCC and CRP were recorded and analysed as to their utility in relation to the final diagnosis. Results: A total of 196 patients underwent an appendicectomy and 41 of these were negative. The specificity of hyperbilirubinaemia for appendicitis overall was 0.83 with a positive predictive value (PPV) of 0.86, compared with CRP (specificity 0.40, PPV 0.75) and WCC (specificity 0.67, PPV 0.85). The area under the receiver operating characteristic curve for bilirubin was 0.6289 compared to 0.6171 for CRP and 0.7219 for WCC. A subgroup analysis of those with complicated appendicitis demonstrated a PPV for bilirubin of 0.66 compared to 0.58 for WCC and 0.34 for CRP in agreement with the literature. Subgroup analysis of hyperbilirubinaemia in simple appendicitis demonstrated a PPV of 0.81 compared to CRP (0.71) and WCC (0.82). Conclusion: Bilirubin had a higher specificity than CRP and WCC overall in patients with appendicitis. Hyperbilirubinaemia had a high PPV in patients with simple appendicitis.
Introduction Acute appendicitis is one of the most commonly encountered surgical conditions with the lifetime risk of having appendicitis estimated at 7%.1,2 Simple acute appendicitis has a low mortality rate of 0.3% but increases to 5–6% when combined with factors such as extremes of age, pre-existing comorbidities and appendix perforation.2 Local and systemic complications such as abdominal abscess formation, sepsis, peritonitis and small bowel obstruction can occur with delayed diagnosis and treatment of a perforated appendix.3 The diagnosis of appendicitis is made on clinical grounds in conjunction with imaging and blood investigations. There is no single clinical test or investigation that can reliably predict appendicitis. The diagnosis of appendicitis can be problematic in those who present with atypical symptoms (20–33%) and there is generally a low threshold for a diagnostic laparoscopy.4 The rate of negative appendicectomy has been estimated at 10–30% and is highest in females of reproductive age (28.7%).5–7 These figures suggest that © 2015 Royal Australasian College of Surgeons
there is room for improvement in the diagnosis of appendicitis to reduce the rate of unnecessary surgery and decrease costs to the health care system. There have been some recent studies that suggest that bilirubin, a cheap and simple biochemical test, is a positive predictor for appendiceal perforation and may be more specific than C-reactive protein (CRP) and white cell count (WCC) in diagnosis of acute appendicitis.6,8–13 The aim of this study was to investigate the usefulness of bilirubin in the diagnosis of appendicitis and to assess its utility in differentiating simple versus complicated appendicitis.
Materials and methods A retrospective chart review was performed on all patients admitted to Nambour General Hospital with suspected appendicitis over a 6-month period from October 2013 to April 2014. Data were collected on patient demographics, results for serological tests taken ANZ J Surg •• (2015) ••–••
2
Sandstrom and Grieve
0.41 0.67 0.80
0.83 0.67 0.40
0.86 0.85 0.75
Table 2 Values of bilirubin, white cell count (WCC) and C-reactive protein (CRP) for differentiating simple appendicitis from non-appendicitis
Bilirubin (n = 184) WCC (n = 181) CRP (n = 72)
Sensitivity
Specificity
Positive predictive value
0.35 0.63 0.77
0.83 0.67 0.40
0.81 0.82 0.71
on admission (liver function tests, WCC, CRP) and histological results. A total of 250 patients were admitted with suspected appendicitis. Two hundred and thirteen patients were included in the study and 37 patients were excluded from the study. Patients were excluded from the study if they did not have liver function tests performed on admission (36 patients), if they were known to have persistently deranged liver function tests or if they had history of known liver disease (one patient). Patients were first divided into two groups according to histology: appendicitis versus no appendicitis. Patients that were discharged without an operation (17) were included in the no appendicitis group. The appendicitis group was then further broken down into simple (acute) appendicitis and complicated (gangrenous/ perforated) appendicitis. Sensitivities, specificities and positive predictive values for total bilirubin, WCC and CRP were calculated for these groups. Additionally, receiver operating characteristic (ROC) curve analysis was performed for bilirubin, WCC and CRP. Hyperbilirubinaemia was defined as a total serum bilirubin level of ≥20 μmol/L, a raised WCC of ≥11 × 109 and a raised CRP as ≥5 mg/L. Statistical analysis was performed using Stata 12 (StataCorp. 2011. Stata Statistical Software: Release 12. StataCorp LP., College Station, TX, USA).
Results The results are presented in Tables 1–4 and Figures 1–3.
Discussion Hyperbilirubinaemia is caused by an increased production or a reduced clearance of bilirubin.6 Bacterial infections, especially those caused by gram-negative pathogens, affect bile production and flow.14 Escherichia coli is the most common organism isolated from peritoneal fluid and through inflammation and subsequent ulceration of the appendix, bacteria can enter the portal circulation.6,8,14,15 Hyperbilirubinaemia in appendicitis is thought to occur through
Bilirubin (n = 87) WCC (n = 84) CRP (n = 33)
Sensitivity
Specificity
Positive predictive value
0.66 0.86 1.00
0.83 0.67 0.40
0.66 0.58 0.34
Table 4 Values of bilirubin, white cell count (WCC) and C-reactive protein (CRP) for differentiating complicated appendicitis from simple appendicitis Sensitivity
Specificity
Positive predictive value
0.65 0.86 1.00
0.65 0.37 0.23
0.30 0.24 0.40
Bilirubin (n = 155) WCC (n = 155) CRP (n = 55)
1.00
Positive predictive value
Sensitivity 0.50 0.75
Specificity
0.25
Bilirubin (n = 213) WCC (n = 210) CRP (n = 80)
Sensitivity
Table 3 Values of bilirubin, white cell count (WCC) and C-reactive protein (CRP) for differentiating complicated appendicitis from non-appendicitis
0.00
Table 1 Values of bilirubin, white cell count (WCC) and C-reactive protein (CRP) for differentiating appendicitis from non-appendicitis
0.00
0.25
0.50 1 - Specificity
0.75
1.00
Area under ROC curve = 0.6289
Fig. 1. Bilirubin: receiver operating characteristic (ROC) curve for total cohort of appendicitis patients.
several underlying mechanisms including intravascular hemolysis and endotoxaemia.8 Lipopolysaccharides associated with E. coli have been shown in vivo to cause cholestasis by affecting hepatocyte uptake and bile acid secretion.6 This endotoxin-induced cholestasis has also been associated with general gastrointestinal perforation and bilirubin increases with severity of intra-abdominal infection.9 Given this relationship between bilirubin and severity, it is hypothesized that bilirubin levels can be used to determine the likelihood of appendiceal perforation. Several studies have reported a relationship between appendiceal perforation and hyperbilirubinaemia. Estrada et al.,10 Hong et al.11 and Sand et al.12 found that patients with perforation or gangrene were significantly more likely to have hyperbilirubinaemia than those with simple acute appendicitis and the risk of appendiceal perforation was three times higher for patients with hyperbilirubinaemia than those with normal serum bilirubin levels. Bilirubin has also been identified as having a higher specificity but lower sensitivity than CRP for appendiceal perforation. Burcharth © 2015 Royal Australasian College of Surgeons
3
0.00
0.25
Sensitivity 0.50 0.75
1.00
Hyperbilirubinaemia in appendicitis
0.00
0.25
0.50 1 - Specificity
0.75
1.00
Area under ROC curve = 0.6171
0.00
0.25
Sensitivity 0.50 0.75
1.00
Fig. 2. C-reactive protein: receiver operating characteristic (ROC) curve for total cohort of appendicitis patients.
found that the odds ratio of having appendicitis in the context of elevated bilirubin on admission was 3.25. They also found hyperbilirubinaemia had a specificity of 0.88 for acute appendicitis and the positive predictive value was 0.91. Emmanuel reported bilirubin to be more specific than CRP for both simple appendicitis and perforated or gangrenous appendicitis. The role of bilirubin in the diagnosis of appendicitis has not been widely researched and the majority of the studies have focussed on hyperbilirubinaemia in perforated appendicitis. This study found that hyperbilirubinaemia had a higher specificity (0.83) for distinguishing between patients with simple appendicitis and patients without appendicitis than WCC and CRP (0.67 and 0.40, respectively). Hyperbilirubinaemia had a higher PPV (0.86) for appendicitis than WCC and CRP (0.85 and 0.75, respectively). In a subgroup analysis of patients with simple appendicitis, hyperbilirubinaemia had a higher PPV than CRP (0.81 versus 0.71) and a similar PPV to WCC (0.82). When distinguishing those patients with complicated appendicitis from those with simple appendicitis, hyperbilirubinaemia had a higher specificity (0.65) compared to WCC and CRP (0.37 and 0.23, respectively). The ROC curve for the total cohort demonstrated that bilirubin was at least as good as CRP as a diagnostic test for appendicitis (area under the ROC curve 0.6289 versus 0.6171) though not as good as WCC (area under the ROC curve 0.7219). This study is limited by its retrospective design making it difficult to reliably exclude pre-existing liver disease. There were a limited number of patients with CRP levels measured on admission which may reflect a clinical bias of severity. Additionally, patients discharged without an operation were included in the non-appendicitis group; however, presentation at another hospital with subsequent appendicectomy could not be excluded.
0.00
0.25
0.50 1 - Specificity
0.75
1.00
Area under ROC curve = 0.7219
Fig. 3. White cell count: receiver operating characteristic (ROC) curve for total cohort of appendicitis patients.
et al. found that elevated total bilirubin levels had a low sensitivity (0.38–0.77) but high specificity (0.70–0.87) for identifying perforated appendicitis while CRP had a higher sensitivity but lower specificity in the same population. Sand et al.12 similarly reported a specificity of 0.86 for bilirubin in perforated appendicitis compared with WCC (0.55) and CRP (0.39). Again, CRP and WCC were more sensitive (0.81 and 0.96, respectively) than bilirubin (0.7). A large study by Giardano et al.13 found that hyperbilirubinaemia had a sensitivity of 0.49 and specificity of 0.82 with an odds ratio of 4.42 for predicting perforation in appendicitis. McGowan et al.16 looked at 1271 patients with appendicitis and reported that CRP and bilirubin were significantly higher in patients with appendiceal perforation with CRP being more sensitive (0.79 versus 0.63) and bilirubin being more specific (0.88 versus 0.63). The above studies only looked at the specificity of bilirubin in appendiceal perforation. A study in Ireland by Emmanuel et al.17 investigated the role of bilirubin in simple appendicitis and © 2015 Royal Australasian College of Surgeons
Conclusion This study highlighted the usefulness of bilirubin in the diagnostic workup of a patient with suspected appendicitis. This study adds to the literature by demonstrating a high PPV for hyperbilirubinaemia in patients with simple appendicitis. Bilirubin is a cheap, readily available biochemical marker that has been shown to be more specific than CRP in patients with appendicitis. In combination with other established clinical, laboratory and radiological tests, adding bilirubin to preliminary investigations could aid in decreasing the rate of negative appendicectomies. This should be further assessed with a prospective study.
References 1. Humes DJ, Simpson J. Acute appendicitis. BMJ 2006; 333: 530–4. 2. Fischer J. Master of Surgery. Philadelphia: Lippincott Williams, 2012. 3. Nomura S, Watanabe M, Komine O et al. Serum total bilirubin elevation is a predictor of the clinicopathological severity of acute appendicitis. Surg. Today 2013; 44: 1104–8. 4. Khairy G. Acute appendicitis: is removal of a normal appendix still existing and can we reduce its rate? Saudi J. Gastroenterol. 2009; 15: 167–70. 5. Jaunoo SS, Hale AL, Masters JP, Jaunoo SR. An international survey of opinion regarding investigation of possible appendicitis and
4
6.
7.
8.
9.
10.
11.
Sandstrom and Grieve
laparoscopic management of a macroscopically normal appendix. Ann. R. Coll. Surg. Engl. 2012; 94: 476–80. Atahan K, Ureyen O, Aslan E et al. Preoperative diagnostic role of hyperbilirubinaemia as a marker of appendix perforation. J. Int. Med. Res. 2011; 39: 609–18. Ma KW, Chia NH, Yeung HW, Cheung MT. If not appendicitis, then what else can it be? A retrospective review of 1492 appendectomies. Hong Kong Med. J. 2010; 16: 12–7. Burcharth J, Pommergaard HC, Rosenberg J, Gogenur I. Hyperbilirubinemia as a predictor for appendiceal perforation: a systematic review. Scand. J. Surg. 2013; 102: 55–60. Hong YR, Chung CW, Kim JW et al. Hyperbilirubinemia is a significant indicator for the severity of acute appendicitis. J. Korean Soc. Coloproctol. 2012; 28: 247–52. Estrada JJ, Petrosyan M, Barnhart J et al. Hyperbilirubinemia in appendicitis: a new predictor of perforation. J. Gastrointest. Surg. 2007; 11: 714–8. Sand M, Bechara FG, Holland-Letz T, Sand D, Mehnert G, Mann B. Diagnostic value of hyperbilirubinemia as a predictive factor for
12.
13.
14. 15.
16.
17.
appendiceal perforation in acute appendicitis. Am. J. Surg. 2009; 198: 193–8. Noh H, Chang SJ, Han A. The diagnostic values of preoperative laboratory markers in children with complicated appendicitis. J. Korean Surg. Soc. 2012; 83: 237–41. Giordano S, Paakkonen M, Salminen P, Gronroos JM. Elevated serum bilirubin in assessing the likelihood of perforation in acute appendicitis: a diagnostic meta-analysis. Int. J. Surg. 2013; 11: 795–800. Miller DF, Irvine RW. Jaundice in acute appendicitis. Lancet 1969; 1: 321–3. Socea B, Carap A, Rac-Albu M, Constantin V. The value of serum bilirubin level and of white blood cell count as severity markers for acute appendicitis. Chirurgia (Bucur) 2013; 108: 829–34. McGowan DR, Sims HM, Shaikh I, Uheba M. The value of hyperbilirubinaemia in the diagnosis of acute appendicitis. Ann. R. Coll. Surg. Engl. 2011; 93: 498. Emmanuel A, Murchan P, Wilson I, Balfe P. The value of hyperbilirubinaemia in the diagnosis of acute appendicitis. Ann. R. Coll. Surg. Engl. 2011; 93: 213–7.
© 2015 Royal Australasian College of Surgeons
