ORIGINAL RESEARCH

International Journal of Surgery 11 (2013) 1114e1117

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International Journal of Surgery

journal homepage: www.journal-surgery.net

Original research

Bilirubin; a diagnostic marker for appendicitisq

N. D’Souza a, *, D. Karim b, R. Sunthareswaran c
a
Poole Hospital, UK
b
Oxford Deanery, UK
c
Stoke Mandeville Hospital, UK

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Every investigation that can contribute towards a diagnosis of appendicitis is valuable to
Received 23 July 2013 the emergency general surgeon. Previous research has suggested that hyperbilirubinaemia is a more
Received in revised form specific marker for both simple and perforated appendicitis than WBC (white blood count) and CRP (C-
29 August 2013
reactive protein), but this investigation is not commonly used to help diagnose appendicitis.
Accepted 13 September 2013
Available online 27 September 2013
Aims: This study investigated whether there is an association between hyperbilirubinaemia and
appendicitis. We also reviewed the diagnostic value of bilirubin in perforated vs simple appendicitis, and
compared it with the serum C-reactive protein (CRP) and white blood cell count (WBC).
Keywords:
Appendicitis
Methods: This single centre, prospective observational study included all patients admitted with right
Hyperbilirubinaemia iliac fossa (RIF) pain who had liver function tests performed. Statistical analysis was performed using
Diagnostic techniques and procedures Fisher’s exact test to compare bilirubin, WBC and CRP levels for normal appendices, simple appendicitis,
Sensitivity and specificity and perforated appendicitis.
Results: 242 patients were included in this study, of whom 143 were managed operatively for RIF pain.
Hyperbilirubinaemia was significantly associated with appendicitis vs RIF pain of other aetiologies
(p < 0.0001). Bilirubin had a higher specificity (0.96), than WBC (0.71) and CRP (0.62), but a lower
sensitivity (0.27 vs 0.68 and 0.82 respectively).
Hyperbilirubinaemia was associated with perforated appendicitis vs simple appendicitis with statistical
significance (p < 0.0001). Bilirubin had a higher specificity (0.82) than both WBC (0.34) and CRP (0.21),
but a lower sensitivity (0.70 vs 0.80 and 0.95 respectively).
Conclusion: Our findings confirm that hyperbilirubinaemia has a high specificity for distinguishing acute
appendicitis, especially when perforated, from other causes of RIF pain, particularly those not requiring
surgery.
Ó 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

1. Introduction incorrect diagnosis incurs the costs and potential complications

In the continued absence of a 100% accurate test for appendicitis,
any investigation that can contribute to its diagnosis is valuable.
Appendicitis remains the most common abdominal surgical emer-
gency, with an incidence between 55.3 (females) and 68.8 (males) to
88 per 100, 000.1,2 A variety of conditions can cause right iliac fossa
(RIF) pain, which do not require surgery. When the diagnosis is not
clear, further investigations may include ultrasound, CT scan or
diagnostic laparoscopy. A negative appendicectomy from an
q Presented at the American Society of Colorectal Surgeons, April 27eMay 1 2013,
Phoenix, Arizona, USA.
* Corresponding author. Department of General Surgery, Poole Hospital, Long-
fleet Road, Poole, Dorset BH15 2JB, United Kingdom. Tel.: þ44 07748496286
(mobile).
E-mail addresses: nige@doctors.net.uk, nigel151@gmail.com (N. D’Souza).
from an unnecessary operation.
Previous retrospective studies have all shown evidence con-
firming the high specificity of hyperbilirubinaemia for perforated
appendicitis3e7; when bilirubin is raised, the likelihood of appen-
dicitis was between 0.7 and 0.87. Two prospective studies have
equivocal8 and positive results.9 Overall, this research has sug-
gested that hyperbilirubinaemia may be a better predictive marker
for perforated appendicitis than white blood cell (WBC) or C-
reactive protein (CRP) levels. Some studies have also demonstrated
an association between hyperbilirubinaemia and simple appendi-
citis.6 Simple appendicitis can be difficult to differentiate from
other causes of RIF pain that do not require surgery; these condi-
tions include mesenteric adenitis in children, benign gynaeco-
logical disease such as ovarian cysts, mittelschmerz or pelvic
inflammatory disease in women, or inflammatory bowel disease in
young adults.

1743-9191/$ e see front matter Ó 2013 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.ijsu.2013.09.006
 ORIGINAL RESEARCH

N. D’Souza et al. / International Journal of Surgery 11 (2013) 1114e1117 1115

Liver function tests (LFTs) are a commonly requested blood test.

Unlike imaging modalities, they are relatively inexpensive, and
carry no risks such as irradiation from CT scans or surgical com-
plications from laparoscopy. A safe, cheap, rapid, widely available,
accurate diagnostic marker for appendicitis would be useful to the
emergency general surgeon to manage suspected appendicitis.

2. Aims

This study seeks to investigate whether there is a statistically

significant association between hyperbilirubinaemia and appen-
dicitis (simple or perforated). By carrying out a prospective study
including patients admitted with RIF pain, we also will investigate
the diagnostic value of bilirubin in differentiating appendicitis from
RIF pain of other causes.
Our secondary outcomes will investigate whether there is an
association between hyperbilirubinaemia and perforated appen-
dicitis, and whether bilirubin is a more specific marker than WBC or
CRP for appendicitis (simple or perforated).
3. Methods
Our prospective, observational study took place in a district general hospital in
the UK from the 1st of January 2012 until 18th July 2012.
All patients admitted under the general surgeons with RIF pain with LFTs
recorded on admission were eligible for inclusion. LFTs are included routinely on
nearly all blood tests performed on surgical patients with abdominal pain. Our
exclusion criteria were a history of liver or haemolytic disease that could lead to
deranged LFTs (hepatitis of any aetiology, Gilbert’s disease, DubineJohnson syn-
drome, benign recurrent intra-hepatic cholestasis or alcoholism). Patients seen with
RIF pain who were discharged after review in the emergency department were not
included.
As part of a registered trust audit, data was collected prospectively. Ethics
approval was not required for audit purposes, and as patient care was routine, no
additional tests were performed. The variables analysed included:
1. Age, sex, time/date of admission.
2. LFTs (liver function tests, including bilirubin), WBC and CRP on admission, with
time and date recorded.
3. Date of operation and operative findings (time between blood tests and surgery
not recorded).
4. The histology of their appendix if removed.
At operation, trust policy is to remove all appendices if an open procedure was
performed. During diagnostic laparoscopy, the appendix is removed if it is inflamed,
or if it is normal and no other pathology is seen to exclude microscopic appendicitis.
Hyperbilirubinaemia was classified as bilirubin levels above 20 mmol/L,
approximately the common upper limit (20.5 mmol/L) of the normal range in most
UK pathology laboratories. Simple appendicitis was defined as any form of inflam-
mation of the appendix mucosa without perforation. Perforated appendicitis was
defined as rupture of the appendix wall seen by the surgeon intra-operatively, or on
histological analysis. WBC above 11, 000 mm3 or CRP above 10 mg/l was classified as
raised.
Categorical variables of high/normal bilirubin and perforated/normal appendi-
citis were analysed with Fisher’s exact test, a p value <0.05 will be significant.
Statistical analysis was carried out using GraphPad Instat 3.10.
4. Results
From the 1st of January 2012 until 18th July 2012, 260 patients
were admitted with RIF pain (see Fig. 1). Patients ranged from 5 to
85 years old, with a mean age of 27.8 years, 39% of whom were
male. Patients with appendicitis had a mean age of 29.4 years, 55%
of whom were male. 18 patients did not have LFTs requested and
were excluded.
99 patients were diagnosed with conditions other than
appendicitis (ovarian pathology, gastroenteritis, abdominal pain of
unknown cause) and were managed non-operatively. 143 patients
with suspected appendicitis underwent surgery; 2 of these pa-
tients were found at operation to have other diagnoses (Crohn’s
disease of the caecum and terminal ileum, caecal diverticulitis).
Fig. 1. Flowchart of patients admitted with right iliac fossa pain.
141 patients had their appendix removed; in 31 cases, histology
was normal (22%). Histology revealed simple appendicitis in 89
(63%) cases, and perforated appendicitis in 19 (14%) cases. The 89
cases of simple appendicitis included acute, gangrenous and
resolving appendicitis.
Of the 99 patients managed non-operatively for other diagnoses,
4 patients (4%) had high bilirubin levels with otherwise normal
LFTs (see Table 1). Their diagnoses included 1 case of diverticulitis, 2
cases of ovarian cysts, and 1 case of abdominal pain of unknown
origin. 2 of the 33 (6%) patients with normal appendix histology or
alternative diagnoses had high bilirubin. 16 of the 74 (22%) of pa-
tients with simple appendicitis had high bilirubin levels, as did 14/
20 (70%) of patients with perforated appendicitis. No patients with
elevated bilirubin had raised ALP, and less than 2% of patients had
mildly elevated transaminases.
To look at the diagnostic value of bilirubin in appendicitis (all
types), we compared patients with appendicitis (simple or perfo-
rated) to patients managed non-operatively, or with normal ap-
pendix histology. We found a specificity of 0.96 for
hyperbilirubinaemia in appendicitis, with a positive predictive
value of 0.86, and an odds ratio of 9.53 (see Table 2). Sensitivity
(0.27) and negative predictive value (0.61) were lower. The speci-
ficity was higher than WBC (0.71) and CRP (0.612). Fisher’s exact
test showed a statistically significant association for bilirubin, WBC
and CRP with appendicitis vs RIF pain of other origin.
Hyperbilirubinaemia in perforated appendicitis vs simple
appendicitis had a specificity of 0.82 for perforated appendicitis, a
sensitivity of 0.70 and an odds ratio of 10.8 (see Table 3). Comparing
bilirubin to WBC and CRP in perforated appendicitis, bilirubin had a
higher specificity (0.82) than both WBC (0.34) and CRP (0.21), but a
lower sensitivity (0.70 vs 0.80 and 0.95 respectively). Fisher’s exact
test showed a statistically significant p value for bilirubin, but not
WBC or CRP, with perforated appendicitis.
We also looked at the mean values for bilirubin, WBC and CRP
within our different categories. We found that all values increased
with progression of appendicitis severity, which was statistically
significant (p < 0.0001) when using the KruskaleWallis test for
non-parametric data (Table 4).
Table 1
Bilirubin levels for each study group.
High Low
bilirubin bilirubin
> 20 mmol/L < 20 mmol/L
Not appendicitis, conservative Mx (N) n ¼ 99 4 95
Normal appendix histology/alternate 1 32
diagnosis (1) n ¼ 33
Non-perforated appendicitis (2) n ¼ 91 16 74
Perforated appendicitis (3) n ¼ 17 14 6
 ORIGINAL RESEARCH

1116 N. D’Souza et al. / International Journal of Surgery 11 (2013) 1114e1117

Table 2 Table 4
Bilirubin vs WBC vs CRP for appendicitis vs RIF pain. Biochemical values for each study group. p values calculated using KruskaleWallis
test. Mean ¼ average, sd ¼ standard deviation, þve ¼ positive test
Appendicitis vs RIF pain of other origin (bilirubin > 20 mmol/L, WBC > 11  103/mL, CRP > 10 mg/L).
Bili 2, 3a 1, Nb Specificity 0.96 (0.92e0.98) Odd’s Ratio 9.53
1 2 3 N p Value
þve 30 5 Sensitivity 0.27 (0.22e0.30) (3.34e29.3)
ve 80 127 PPV 0.86 (0.70e0.95) Fisher’s 2 sided Bili Mean 7.32 14.69 25.88 9.71 p < 0.0001
NPV 0.61 (0.59e0.63) p value < 0.0001 sd 3.28 9.64 19.61 6.65
þve 0 17 12 4
WBC 2, 3 1, N Specificity 0.71 (0.65e0.76) Odd’s Ratio 5.11
ve 31 74 5 89
þve 75 39 Sensitivity 0.68 (0.61e0.75) (2.85e9.20)
ve 35 93 PPV 0.66 (0.59e0.72) Fisher’s 2 sided WBC Mean 10.62 13.08 14.97 8.99 p < 0.0001
NPV 0.73 (0.67e0.76) p value < 0.0001 sd 5.43 4.74 6.2 3.23
þve 11 59 13 24
CRP 2, 3 1, N Specificity 0.62 (0.56e0.66) Odd’s Ratio 7.29
ve 20 32 4 69
þve 90 50 Sensitivity 0.82 (0.75e0.88) (3.85e13.9)
ve 20 81 PPV 0.64 (0.59e0.69) Fisher’s 2 sided CRP Mean 23.62 63.33 131.64 29.3 p < 0.0001
NPV 0.80 (0.73e9.86) p value < 0.0001 sd 49.18 81.71 101.98 56.78
a þve 9 72 16 38
Appendicitis (simple and perforated).
b ve 21 19 1 55
Not appendicitis (normal appendix histology, alternate diagnoses).

5. Discussion which may be of a gastrointestinal origin (E. coli in diverticulitis) or

from other sources such as pneumonia, endocarditis, pyelone-
Bilirubin is not commonly known to be a relevant marker in phritis and soft-tissue abscesses.17
appendicitis. However, previous studies have found hyper- The prospective nature of our study, with inclusion of all pa-
bilirubinaemia to be a marker with high specificity for perforated tients with RIF pain, revealed an original findingdthat hyper-
appendicitis. Adult bilirubin levels in the adult surgical population bilirubinaemia predicts appendicitis (simple and perforated) in
are usually raised due to liver or gallbladder problems. Gilbert’s patients admitted with RIF pain. Given the large volume of patients
syndrome may cause an idiopathic, isolated unconjugated hyper- with RIF pain seen by an emergency general surgical team, we felt it
bilirubinaemia. However, the prevalence of Gilbert’s syndrome is was important to include this non-operative group in our study
expected to be around 6%,10 which is considerably less than the design. The specificity of hyperbilirubinaemia of 0.96 for appendi-
prevalence we found in simple appendicitis (18.7%) and perforated citis is very high, and should alert the clinician to the possibility of
appendicitis (70.6%). this diagnosis.
Hepatic dysfunction as a result of bacterial infection or sepsis Our secondary outcome confirmed that there is a high specificity
without direct invasion of the liver, has already been well of bilirubin (0.82) for perforated appendicitis, matching results from
described.11,12 The possible aetiologies include gram negative the literature3e9 (see Table 5). Our odds ratio of 10.8 is higher
sepsis, shock and ischaemic liver, severe trauma or gut barrier than has so far been reported in most papers (range 2.96e9.85). WBC
failure.13 Gram negative organisms, with Escherichia coli in partic-
ular, have been shown to produce endotoxins that affect bile flow in Table 5
Summary of previous studies.
rat liver models.14,15 None of the patients in our study had ischae-
mic liver, or septic shock. Study Type of study Sample Findings
In appendicitis, compromised appendix wall integrity leads to size
translocation of bacteria and endotoxins from the appendix lumen Estrada Retrospective 170 Hyperbilirubinaemia (17.1 mmol/L)
into the portal system. Inflammatory cytokines may then travel to et al., 20074 and perforated appendicitis
the liver, inducing intrahepatic cholestasis. Research has also  p ¼ 0.031, Odds ratio 2.96 (95%
confidence interval 1.11e7.6)
shown that E. coli endotoxin causes dose dependent cholestasis,16
Sand Retrospective 538 Hyperbilirubinaemia (26.5 mmol/L)
which would explain our findings of increased bilirubin levels et al., 20093 and perforated appendicitis
with progressive appendicitis severity. It is possible that bilirubin  p < 0.05, Specificity 86%
may be raised in other sources of gram-negative related sepsis, Kaser Retrospective 725 Hyperbilirubinaemia (20 mmol/L)
et al., 20105 and perforated appendicitis
 p ¼ 0.05, Specificity 78%
Table 3 Atahan Retrospective 351 Hyperbilirubinaemia (17.1 mmol/L)
Bilirubin vs WBC cs CRP for perforated appendicitis vs simple appendicitis. þve/ et al., 20117 and perforated appendicitis
ve ¼ high or low test scores (bilirubin > 20 mmol/L, WBC > 11  103/mL,  p ¼ 0.000, Specificity 87.21%
CRP > 10 mg/L). 95% confidence intervals in brackets. Emmanuel Retrospective 472 Hyperbilirubinaemia (20.5 mmol/L)
et al., 20116 and simple appendicitis
Perforated vs simple appendicitis  p < 0.001, Specificity 88%
Bili 3a 2b Specificity 0.82 (0.77e0.86) Odd’s Ratio 10.79
þve 14 16 Sensitivity 0.70 (0.48e0.86) (3.22e37.8) Hyperbilirubinaemia and perforated
ve 6 74 PPV 0.47 (0.32e0.58) Fisher’s 2 sided appendicitis
NPV 0.93 (0.87e0.96) p value < 0.0001  p < 0.001, Specificity 70%
Khan, 20089 Prospective 110 Hyperbilirubinaemia (18.81 mmol/L)
WBC 3 2 Specificity 0.34 (0.30e0.37) Odd’s Ratio 2.10
and perforated appendicitis
þve 16 59 Sensitivity 0.80 (0.58e0.93) (0.59e8.19)
 Specificity 100%
ve 4 31 PPV 0.21 (0.16e0.25) Fisher’s 2 sided
Beltran Prospective 134 Hyperbilirubinaemia (17.86 mmol/L)
NPV 0.89 (0.76e0.96) p value ¼ 0.29
et al., 20098 and perforated appendicitis
CRP 3 2 Specificity 0.21 (0.17e0.22) Odds Ratio 5.09  Specificity 51%, Sensitivity 57%
þve 19 71 Sensitivity 0.95 (0.76e1.00) (0.654e108.29)
ve 1 19 PPV 0.21 (0.17e0.22) Fisher’s 2 sided NB e Values representing the best
NPV 0.95 (0.76e1.00) p value ¼ 0.116 sensitivity and specificity for all
a tested variables were calculated
Perforated appendicitis.
b based on ROC curve analysis
Simple appendicitis.
 ORIGINAL RESEARCH
N. D’Souza et al. / International Journal of Surgery 11 (2013) 1114e1117
and more recently CRP are useful laboratory blood tests,18e21 and
indeed have a much higher sensitivity than bilirubin for appendi-
citis, but a lower specificity. This confirms the use of hyper-
bilirubinaemia as a rule-in, not rule-out test for appendicitis.
The diagnosis of appendicitis is still based on a patient’s clinical
presentation, and the judgement of the emergency surgeon. The
most common investigative adjuncts are blood tests (WBC and
more recently, CRP), urinalysis and imaging. CT has a very high
diagnostic accuracy (93e98%22) but is used less often in Europe.23
This is due to concerns over irradiation of the predominantly
young patient population with appendicitis. Cost also may be a
factor. While CT has high diagnostic accuracy for appendicitis, this
study has confirmed that hyperbilirubinaemia can predict perfo-
ration with high specificity. In Europe, diagnostic laparoscopy now
plays an increasingly important role in the evaluation of RIF pain. As
appendicectomy is carried out routinely during these operations,
there has been a concurrent increase in the negative appendicec-
tomy rate in some trusts.24,25 A correct pre-operative diagnosis
could reduce the number of possibly unnecessary operations with
the costs of theatre time, hospital stay and time off work to recover,
as well as the risks of complications.
Methodological limitations to this study included the possibility
of discharged patients presenting with appendicitis at other hos-
pitals. A multivariate statistical analysis was beyond the resources
of this study. Our recruited numbers were limited by the duration
of the investigator’s surgical rotation; an adequately powered study
would require a sample size of 418 patients.
6. Conclusion
Our findings confirm that hyperbilirubinaemia has a high
specificity for distinguishing acute appendicitis, especially when
perforated, from other causes of RIF pain, particularly those not
requiring surgery.
Ethical approval
Not required.
Funding
None.
Author contribution
Nigel D’Souza: study design, data collection, data analysis,
writing.
Diallah Karim: data collection.
Rame Sunthareswaran: data analysis.
Conflict of interest
None.
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