Bilirubin - A Predictor Of Appendiceal Perforation

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1 Original Article Bilirubin - A Predictor Of Appendiceal Perforation Nandhini. N.E, Ponnudhali. D, Evangeline Jones 1 Final year Postgraduate Student, Dept. of Biochemistry, Vinayaka Missions's Kirupananda Medical College, VMRF(DU) Salem, TN. 2 Associate Professor, Dept. of Biochemistry, Vinayaka Missions's Kirupananda Medical College,VMRF(DU) Salem, Tamilnadu. 3 Professor and HOD, Vinayaka Missions's Kirupananda Medical College, Department of Biochemistry, Salem, VMRF(DU) Tamilnadu. ABSTRACT Introduction: Acute appendicitis is the most common abdominal emergency. Any delay in the diagnosis and treatment, could result in life threatening complications like perforated appendicitis. Though non-specific tests like WBC count, C reactive protein are routinely done, they are not of much diagnostic value. Recent studies have shown that increase in pre-operative serum bilirubin levels could predict the occurrence of perforated appendicitis. Aims and objectives: 1) To assess the serum bilirubin (Total, Direct, Indirect) levels in acute and perforated appendicitis. 2) To look for any associated changes in liver enzymes. 3) To analyze the sensitivity and specificity of serum bilirubin and its utility as a diagnostic/ predictive marker of perforated appendicitis. Materials and methods: A Retrospective study - Medical records of sixty patients who had underwent open appendicectomy during the last one year were scrutinized and all the relevant information noted. 30 patients who underwent surgery for simple appendicitis formed group patients who underwent surgery for perforated appendicitis formed group 2. Their pre-operative laboratory serum bilirubin values and other liver parameter values were collected and analyzed. All the above parameters were compared between two groups using independent student 't' test and ROC curve obtained for Bilirubin,with SPSS 23 software. Results: Total bilirubin levels were significantly increased in patients with perforated appendicitis (p=.000) compared to patients with simple appendicitis. Similar increase in serum direct and indirect bilirubin levels (p=.000) were noticed in perforated appendicitis patients. Total Bilirubin (cut-off: 0.80mg/dl) has sensitivity 80% and specificity 75%. Conclusion: Assessing serum bilirubin levels pre-operatively could have significant value in predicting appendicular perforation. Serum bilirubin being an inexpensive and routinely done test in all labs, with its high sensitivity and specificity, better qualifies as a diagnostic marker for perforated appendicitis even in a rural care centre. Key words: Serum total bilirubin, acute appendicitis, Alvarado's score, perforated appendicitis INTRODUCTION: he most common cause of acute abdomen in young adults in acute appendicitis. Delay in diagnosis and surgery for this Tcondition may lead to various complications like perforation, abdominal abscess, urinary retention, small bowel obstruction and peritonitis causing an increase in morbidity and even mortality of the patients. Incidence of perforated appendicitis in 1 adults is about 13-37%. Every investigation that can contribute towards a diagnosis of appendicitis 2 is valuable to emergency surgeon. Address for correspondence: Dr.D.Ponnudhali, Associate Professor, Department of Biochemistry, Vinayaka Missions Kirupananda Variyar Medical College, Salem. id: ponnudhalid@gmail.com Ph. No:

2 Various markers such as WBC count are identified for diagnosing acute appendicitis. WBC count is not specific for acute appendicitis and CRP may be only significantly raised once perforation takes 3 place. So these markers are used along with various diagnostic scores such as Alvarado score, Modified Alvarado score, Pediatric Appendicitis score(pas) for diagnosing acute appendicitis. But none of them evaluates the risk of perforation in 4 acute appendicitis. Though various imaging modalities like computed tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasonography may help in early diagnosis of perforated appendix, they may not be readily available in many health centers and also time 5, 6,7,8 consuming. In such condition clinical and laboratory investigations may be the only, cheaper and readily available options for diagnosis. Recent studies have shown that elevated serum bilirubin is a useful predictor of appendiceal perforation. The present study was conducted to assess relationship between appendicular perforation and serum bilirubin levels, which could aid in preoperative diagnosis of perforated appendicitis. MATERIALS AND METHODS : Study Design: Our study had been conducted in Government Hospital, Bhavani and Vinayaka Missions's Kirupananda Variyar Medical College Hospital, Salem. It was a retrospective study conducted in 60 patients admitted for appendicectomy surgery during the period of August July They were divided into 2 groups. Group 1:30 patients who underwent surgery for simple appendicitis. Group 2: 30 patients who underwent surgery for perforated appendicitis. We collected LFT reports from records of 60 patients who were admitted with acute abdomen out of which 30 patients were found to have perforated appendicitis and 30 patients were found to have simple appendicitis without any perforation or gangrenous changes during surgery. Patients were excluded from the study if they did not have LFTs performed on admission, if they had a history of confirmed hepatitis or liver disease or if they were known to have persistently deranged LFTs. Patients undergoing interval appendectomies, appendectomies for other indications and patient with negative appendectomies confirmed on histological report were excluded from the study. Other exclusion criteria were patient with risk factors for hepatic disease such as alcoholism, a history of viral hepatitis, Gilbert's disease, Dubin- Johnson syndrome, benign recurrent intra-hepatic cholestasis, and other documented biliary, hemolytic or liver diseases associated with hyperbilirubinemia. STATISTICAL ANALYSIS: Statistical analysis was done using the software SPSS version 23 and data expressed as mean ± SD. Differences in mean between the 2 groups were analyzed using independent t test. Comparisons were made between two groups of patients: those with simple acute appendicitis and those with appendiceal perforation. Mean levels of bilirubin, and other LFTs were compared between groups. The sensitivities, specificities, positive predictive values and negative predictive values of serum 179

3 bilirubin for both simple acute appendicitis and Table 2 : Mean and standard deviation for other perforated appendicitis was calculated. The liver parameters in patients with acute receiver operating characteristic (ROC) curve for appendicitis without perforation (group 1) and bilirubin was obtained acute appendicitis with perforation (group 2) RESULTS : The Bilirubin levels (total, direct, indirect) and other liver parameters were analyzed in 30 patients with simple appendicitis and 30 patients with perforated appendicitis. The mean and standard deviations of bilirubin (total, direct, indirect) levels are depicted in Table 1. There is a significant increase in the total bilirubin levels (1.0 ± 0.28 mg/dl) in group 2 patients, compared to the patients (0.61 ± 0.18 mg/dl) in group 1 (p=0.001). There is a significant increase in the serum direct and indirect bilirubin levels (0.30 ± 0.13 mg/dl, 0.73 ± 0.19mg/dl,p=0.001) in group 2 patients, compared to the patients in group 1 (0.16 ± The ROC curve analysis for serum total bilirubin levels was done, with the Area Under the Curve (AUC) being The sensitivities, specificities, PPVs and NPVs for different cut-off levels of serum bilirubin were tabulated. At the optimum cut-off level -0.8 mg/dl of serum total bilirubin, sensitivity and specificity were 80% and 75% respectively. Figure 1 depicts the ROC Curve of total bilirubin mg/dl,0.44 ± 0.16mg/dl,p=0.000). Table 1: Mean and standard deviation for Bilirubin in patients with acute appendicitis without perforation (group 1) and acute Table 3 depicts the cut off values of serum total bilirubin with their sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) appendicitis with perforation (group 2). Table 3: Sensitivity and Specificity of serum total bilirubin *P value <0.05 is considered significant. We compared the other liver function tests in both the groups. There was not any significant difference and they were with in normal limits in both the groups. Table 2 depicts the other liver functions tests in group 1 and group

4 Fig 1. ROC Curve for total bilirubin DISCUSSION: Acute appendicitis appears to be the most common cause for Acute Surgical abdomen with appendicular perforation being the most significant 9,10,11,12 complication. The major organisms commonly seen in normal appendix as well as acute appendicitis are Eschericia coli, Bacteroids fragilis 13 and various facultative anaerobes. In acute appendicitis and perforated appendicitis there is a compromised wall integrity resulting in 14 following changes. Acute appendicitis/ appendicular perforation Translocation of bacterial endotoxins/cytokines (from appendicular lumen to portal system thereby liver) Alters the physiology of biliary excretion. Induces intrahepatic cholestasis Hyperbilirubinemia Lipopolysaccharides associated with E. coli can affect hepatocyte uptake and bile acid secretion15. The patients with perforated appendicitis, show a proinflammatory cytokine and nitric oxide triggered cholestasis by impairing hepatocellular 16 and bile duct function. In our study we have found that patients with perforated appendicitis had hyperbilirubinemia with no changes in enzyme levels.there are few 17,18 other studies, having reported similar findings. A retrospective analysis conducted by Atahan et al., found that symptom duration (p=0.002), total bilirubin (p=0.000) and elevated leucocyte counts (p=0.011) were significant independent variables for identifying acute perforated appendicitis 19 against the suppurative ones. A retrospective cohort study performed by Kaser etal., in two centers compared the efficacies of hyperbilirubinemia, CRP, leucocyte count and age 20 as markers of perforated appendicitis. They came to the conclusion that hyperbilirubinemia is a statistically significant marker of perforated appendicitis. We have also assessed the AUC in ROC curve analysis to determine the appropriate levels of serum bilirubin at which it identifies perforated appendicitis. As the AUC for total bilirubin is >0.8, it can be considered as a marker to predict the occurence of perforation among patients with acute appendicitis. At the cut-off level of 0.8mg/dl, serum total Bilirubin has a sensitivity of 80% and specificity of 75%. Its utility as a predictive biomarker has to be confirmed by further prospective studies conducted in larger populations. 181

5 CONCLUSION: It is evident that Serum Bilirubin has a remarkable role in identifying patients presenting with perforated appendicitis. Serum Bilirubin with all its beneficial attributes, is quite cheap, feasible and an easily available laboratory test even in peripheral health care centers. Hence it could be a useful biomarker either alone or in combination with other radiological methods, in the preoperative diagnosis of perforated appendicitis. REFERENCES: 1. Stumvoll M, Goldstein BJ, van Haften TW. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet 2005; 365: A. Q. Khan, Anirudha Patil, Praful Pawar. Role of Hyperbilirubinemia as a Diagnostic Predictor of Appendicular Perforation. International Journal of Science and Research. 2014; 3(12): Ghimire P, Thapa, Yogi N, Ghimire P. Role of serum bilirubin as a marker of acute gangrenous appendicitis. Nepal Journal of Medical Sciences.2013;27(4): Salvatore Giordano, Markus Paakkonen Paulina Salminen, Juha M Gronroos. International Journal Of Surgery ;23(7): N.D'Souza, D.Karim, R.Sunthareswaran. Bilirubin : A new diagnostic marker of appendicitis. International journal of surgery. 2013; 11(2): Andrew Emmanuel, Peter Murchan, Ian Wilson, Paul Balfe. The value of hyperbilirubinaemia in the diagnosis of acute appendicitis. Ann R CollSurgEngl 2011; 93: Amalesh T, Shankar M, Shankar R: CRP in acute ap- pendicitis is it a necessary investigation? International journal of surgery 2004;2: Khan MN, Davie E, Irshad K: The role of white cell count and C-reactive protein in the diagnosis of acute appendicitis. J Ayub Med Coll Abbottabad 2004;16: dedombal FT, Leaper DJ, Staniland JR, et al: Com- puter-aided diagnosis of acute abdominal pain. BMJ 1972;2: O' Connel PR. The Vermiform Appendix. In: Williams NS, BulstrodeCJK, O'Connell PR (Ed.). Bailey and Love's - Short practice of surgery.2008; 25: Smink DS, Soybel DI. Appendix and Appendectomy. In: Zinner MJ, Stanely W ( e d s ) M a i n g o t s a b d o m i n a l operations.2007;11: Balthazar EJ, Megibow AJ, Siegel SE. Appendicitis: prospective evaluation with high resolution CT. Radiology 1991;180: Rao PM, Boland GW.Imaging of acute right lower abdominal quadrant pain. ClinRadiol 1998;53: Bixby SD, Lucey BC, Soto JA: Perforated versus nonperforated acute appendicitis: accuracy of multide- tector CT detection. Radiology 2006;6:

6 14. Mohammad Vaziri, Abdolreza Pazouki, Zeinab Tamannaie, Farshid Maghsoudloo, Mohadeseh Pishgahroudsari, Shahla Chaichian. Comparison of pre-operative bilirubin level in simple appendicitis and perforated appendicitis. Medical Journal of the Islamic Republic of Iran.2013;27(3): Green RM, Beier D, Gollan JL: Regulation of hepatocyte bile salt transporters by endotoxin and inflammatory cytokines in rodents. Gastroenterology 1996; 111: Whiting JF, Green RM. TNF-alfa decrease hepatocyte bile salt uptake and mediated e n d o t o x i n i n d u c e d c h o l e s t a s i s. Hepatology.1995;22: Khan S: Elevated serum bilirubin in acute appendicitis: a new diagnostic tool. Kathmandu Univ Med J.2008; 6: Atahan K, Ureyen O, Aslan E.Preoperative diagnostic role of hyperbilirubinaemia as a marker of appendix perforation. The Journal of International Medical Research. 2011;39: Käser SA, Fankhauser G, Willi N. Creactive protein is superior to bilirubin for anticipation of perforation in acute appendicitis. Scand J Gastroenterology 2010;45: Estrada JJ, Petrosyan M, Barnhart J: Hyperbilirubinemia in appendicitis: a new predictor of perforation. J GastrointestSurg 2007;24(11): Received on: Revised on: Accepted on: