|Year : 2014 | Volume
| Issue : 1 | Page : 1-5
Hyperbilirubinemia, C-reactive protein and ultrasonography as predictors of appendiceal perforation: A prospective study
Mumtaz Din Wani1, Shabir Ahmad Mir1, Jahangeer Ahmad Bhat2, Salma Gul3, Umar Maqbool1, Hakim Adil Moheen4
1 Department of Surgery, Government Medical College, Srinagar, Jammu and Kashmir, India
2 Department of Radiodiagnosis, Government Medical College, Srinagar, Jammu and Kashmir, India
3 Department of Internist, Government Medical College, Srinagar, Jammu and Kashmir, India
4 Department of Post Graduate Scholar, BS, Kashmir University, Jammu and Kashmir, India
|Date of Web Publication||21-May-2014|
Mumtaz Din Wani
Department of Surgery, Government Medical College, Srinagar, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Background: Acute appendicitis is the most common cause of acute abdomen and subsequent surgery. The diagnosis is essentially based on the clinical grounds and as a result misdiagnosis is a common and crucial problem in general surgery. Delayed or wrong diagnosis in patients with appendicitis can result in perforation and consequently increased morbidity and mortality. Serum bilirubin and C-reactive protein (CRP) have been shown to indicate perforation in appendicitis.
Aim: The purpose of this study was to evaluate the role of hyperbilirubinemia, CRP and ultrasonography (USG) as predictors for appendiceal perforation. Materials and Methods: This study consisted of patients admitted with the clinical suspicion of acute appendicitis. The study finally included a group of those 100 patients who had histologically proven appendicitis. Subsequent to hospital admission all patients underwent thorough physical examination and routine lab exams. Preultrasound clinical diagnosis was made based on medical history, physical examination as well as laboratory findings. Real-time, high-resolution (5 MHz, 7.5 MHz) graded compression ultrasound examination was performed by a senior radiologist after a clinical diagnosis was made. Results: Serum bilirubin and CRP were raised in significant number of patients with appendiceal perforation compared to the patients of appendicitis without perforation. Thirty-three of 42 patients with perforated appendix had bilirubin ≥1.5 mg/dl (P < 0.0001). Sensitivity of serum bilirubin in predicting perforation was 78.57%, while as specificity was 89%. Thirty-five of 42 patients with perforated acute appendicitis had raised CRP levels (P < 0.0001). Sensitivity and specificity of CRP in predicting perforation were 83% and 74%, respectively. Abdominal USG in patients with diagnosis of perforated acute appendicitis has a sensitivity of 64.28% and specificity of 79.3% (P < 0.0001). Conclusion: Bilirubin, CRP and ultrasound are effective for differentiation of perforated from nonperforated appendicitis. Bilirubin, CRP and USG are important preoperative biochemical and sonographic markers of perforation, respectively in appendicitis.
Keywords: Appendix, C-reactive protein, hyperbilirubinemia, perforation, ultrasonography
|How to cite this article:|
Wani MD, Mir SA, Bhat JA, Gul S, Maqbool U, Moheen HA. Hyperbilirubinemia, C-reactive protein and ultrasonography as predictors of appendiceal perforation: A prospective study. Saudi Surg J 2014;2:1-5
|How to cite this URL:|
Wani MD, Mir SA, Bhat JA, Gul S, Maqbool U, Moheen HA. Hyperbilirubinemia, C-reactive protein and ultrasonography as predictors of appendiceal perforation: A prospective study. Saudi Surg J [serial online] 2014 [cited 2020 Aug 5];2:1-5. Available from: http://www.saudisurgj.org/text.asp?2014/2/1/1/132891
| Introduction|| |
Vermiform appendix though described anatomically to be vestigial, but is one of the most important surgically concerned organs in the human body. There are many pathological conditions involving appendix and acute appendicitis is the most common. It can present at all ages, although it occurs more frequently during the second and third decades of life. It is easy to diagnose typical cases of this disease, but atypical cases prove to be a very great diagnostic challenge for a clinician. This resulted in negative appendicectomy rate of 20-30% and has been considered acceptable, but even removal of a normal appendix carries a definite morbidity. Acute uncomplicated appendicitis can be difficult to distinguish clinically from perforated appendicitis, especially in the elderly and in children. , The mortality associated with simple acute appendicitis is reported to be 0.3%, but increases to 6% in cases with perforation.  The radiological modalities such as computed tomography (CT) and ultrasonography (USG) are effective in supplementing the diagnosis of acute appendicitis. , Several studies have found bilirubin to be a useful serological marker for predicting an acute appendicitis , and appendiceal perforation. ,,,, High-resolution; graded compression ultrasound has been reported to be useful for the diagnosis by of appendicitis. The use of ultrasound in the diagnosis of acute appendicitis was first popularized Puylaert in1986. In graded compression technique, uniform pressure is applied in the right iliac fossa by a hand held ultrasound transducer. Normal and gas filled loops of the intestine are either displaced from the field of vision or compressed between anterior and posterior abdominal walls. Inflamed appendix being incompressible is thus optimally seen as a blind-ended tubular structure with laminated wall arising from the base of cecum. It is aperistaltic, noncompressible and its diameter should be >6 mm. Appendicoliths appear as bright echogenic foci with distal acoustic shadowing, and their visualization is another contributory finding. Similarly, there may be increased echogenicity of the periappendiceal fat. In this study, we investigated the role of bilirubin, C-reactive protein (CRP) and high-resolution USG in the diagnosis of perforation in acute appendicitis and recorded their sensitivity and specificity.
| Materials and Methods|| |
This prospective study was carried out in the Postgraduate Department of Surgery over a period of 18 months from January 2012 to June 2013. This study consisted of patients admitted with the clinical suspicion of acute appendicitis. Most of the patients presented primarily to our institution and the rest of the patients were referred to us. The study finally included a group of those 100 [Table 1] patients who had histologically proven appendicitis and others were excluded. Subsequent to hospital admission all patients underwent thorough physical examination and routine laboratory examinations . Preultrasound clinical diagnosis was made based on medical history, physical examination as well as laboratory findings. Duration of symptoms was noted [Table 2]. The most common symptom was pain in the right iliac fossa. Real-time, high-resolution (5 MHz, 7.5 MHz) graded compression ultrasound examination was performed by senior radiologists after a clinical diagnosis was made. The diagnosis of perforation on USG was made by visualization of loculated pericecal fluid, phlegmon or abscess, prominent pericecal or periappendiceal fat and circumferential loss of the submucosal layer of the appendix. 
Sonographic films were taken and findings were recorded. Preoperatively patients were kept nil per oral and received intravenous fluids along with intravenous antibiotics. No analgesic was given preoperatively. Surgical outcome of all patients was recorded separately. Definitive diagnosis was based on histopathological examination. Patients undergoing interval appendectomies and patient with negative appendectomies confirmed on histological report were excluded from the study. Other exclusion criteria were patients 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.
| Results|| |
All patients included were operated for appendicitis, which were verified by pathological examination. Of total 100 patients included in this study, 42 cases turned out to be perforated appendicitis on intraoperative/histopathologic study.
Serum bilirubin [Table 3] was elevated (>1.5 mg/dl) in 33 patients out of 42. Six (06) patients of nonperforated appendicitis had elevated serum bilirubin levels (>1.5 mg/dl). 52 patients of nonperforated appendicitis had serum bilirubin <1.5 mg/dl. Sensitivity of serum bilirubin in predicting perforation was 78.57% while as specificity was 89%. Serum bilirubin was >1.5 mg/dl in significantly higher number of patients with perforated appendicitis compared to patients with nonperforated appendicitis. Serum bilirubin is raised not only in perforated cases but also in simple cases of appendicitis. However rise in serum bilirubin level is more in perforated or gangrenous cases of appendicitis and our cut-off value of 1.5 mg/dl for serum bilirubin is an arbitrarily chosen value signifying that values above 1.5 mg/dl more often occur in cases perforated or gangrenous appendicitis and values <1.5 mg/dl occur more often in cases of simple appendicitis. Therefore, few false negative and positive cases are expected to occur. False negative cases (09) might be explained by the possible decrease in counts of Escherichia More Details coli with intravenous antibiotics before the hepatocytemicrocirculatory compromise. False negative cases might also have occurred due to high threshold of red blood cells to E. coli induced hemolysis. The serum bilirubin values for patients with perforated appendicitis ranged from 20.52/L to 42.75 μmol/L with the average value of 29.07 μmol/L. CRP marker was higher in significant number of patients with perforated appendicitis (P < 0.0001). CRP [Table 4] was elevated in 35 cases of perforated appendicitis (value >10 mg/dl). Sensitivity and specificity of CRP in predicting perforation were 83% and 74% respectively. CRP levels fail to rise in some cases of inflammation though the reason for this has not been found undoughtfully. It also fails to rise in cases of hepatocellular dysfunction. These might explain the false negative cases.
All patients of suspected acute appendicitis were subjected to high-resolution graded compression USG. The diagnosis of perforation on USG [Table 5] and [Table 6] was made by visualization of loculated pericecal fluid, free intraperitoneal fluid, phlegmon or abscess, prominent pericecal or periappendiceal fat and circumferential loss of the submucosal layer of the appendix.
Of these, USG accurately diagnosed, 27 patients of acute appendicitis with perforation, which were later confirmed on laparotomy and subsequent histopathological examination, 15 patients were falsely interpreted as negative for perforated appendicitis and 12 were falsely interpreted as positive for perforated appendicitis. Perforation was more common in younger age group. USG has a sensitivity of 64.28% and specificity of 79.31% for diagnosis of acute appendicitis with perforation (P < 0.0001). False results (negative/positive) could be explained by operator dependence of USG. Obese and poorly prepared patients being less suitable for USG examination can explain the false negative cases. Minimal free fluid due to ovulation is observed normally in females. This can be wrongly (false positive) interpreted as a feature of perforated appendicitis. Ultrasound is effective for differentiation of perforated from nonperforated appendicitis.
| Discussion|| |
Despite being one of the most frequent diagnoses among surgical emergencies, acute appendicitis continues to pose significant diagnostic problems. The diagnosis of acute appendicitis in most cases is based on clinical history and physical exploration. , Among young male patients the negative appendicectomy rate is relatively low, while for women of childbearing age, the figure may be as high as 30-50%. ,, The difficulty of diagnosing acute appendicitis in old age is reflected by the high incidence of perforation, 60-90% in many reports rather than by a high rate of negative appendicectomy. , Diagnosis is also difficult during pregnancy and may result in both maternal and fetal mortality. As the incidence of perforation is usually proportional to the duration of the disease process, traditional teaching has encouraged surgeons to operate even when the diagnosis is probable rather than wait until it is certain.
This teaching has been challenged by some who have shown that intensive observation in hospital can decrease the incidence of negative appendicectomy without increasing the rate of perforation. Prolonged observation is, however, not an ideal solution as it is expensive to the health services.
The morbidity and mortality rates associated with appendicitis are greatly increased when perforation ensues, wound infection rates may treble, intra-abdominal abscess formation increases 15-fold and mortality may be 50 times greater. Appendiceal perforation can also cause tubal infertility.  It is therefore obvious that the aim of the surgeon must be to prevent perforation at any price. The price is the high rate of removal of a histologically normal appendix, which is not inexpensive as it carries with it a complication rate not much lower than that after removal of a pathological appendix. The operation of negative appendicetomy is no exception to usual immediate postoperative complications, especially if comorbidities are associated additional patients may suffer late complications such as intestinal obstruction, incisional hernias and sterility due to fimbrial adhesions. ,,, It appears; therefore, that surgeons have chosen for themselves a surgical security zone, which allows them to accept a 15-30% negative laparotomy rate with impunity. The diagnosis of perforation on USG was made by visualization of loculated pericecal fluid, phlegmon or abscess, prominent pericecal or periappendiceal fat and circumferential loss of the submucosal layer of the appendix.  The appendicitis with perforation was confirmed on operation table and subsequent histopathological examination in all cases. In acute gangrenous appendicitis, there is more marked enlargement of appendix associated with inflammatory pooling of liquid, edema of wall and evidence of increased intraluminal pressure (Takada et al., 1986).  In a retrospective study on 161 consecutively registered children from two centers who had acute appendicitis and had undergone ultrasound, images were reviewed for appendiceal size, appearance of the appendiceal wall, changes in periappendiceal fat, and presence of free fluid, abscess, or appendicolith. The surgical report served as the reference standard for determining whether perforation was present. The patients included were 94 boys and 67 girls (age range, 1-20 years; mean, 11 ± 4.4 [standard deviation] years). Appendiceal perforation rate was significantly higher in children younger than 8 years (62.5%) compared with older children (29.5%). Sonographic findings associated with perforation included abscess (sensitivity, 36.2%; specificity, 99%), loss of the echogenic submucosal layer of the appendix in a child younger than 8 years (sensitivity, 100%; specificity, 72.7%), and presence of an appendicolith in a child younger than 8 years (sensitivity, 68.4%; specificity, 91.7%). They concluded that ultrasound is effective for differentiation of perforated from no perforated appendicitis in children. 
In our study, sensitivity of USG was 64.28%, specificity 79.31% for perforated appendicitis. Ozgunger et showed that sensitives of USG was 42.1% in nonperforated appendicitis, and 65% in perforated appendicitis.  The sensitivity and specificity of CRP and bilirubin are determined by threshold values. It has been shown that during appendicitis, an ulceration of the mucosa in the appendix occurs due to the inflammation which facilitates bacterial translocation from the appendix to the portal blood system.  The most common bacteria to infect the appendix is E. coli. When E. coli reaches the hepatic tissue through the portal venous system, animal models have shown that the bacteria interferes with the hepatocyte microcirculation, which induces damage to the liver cells and compromises excretion of bile acids into the bile canaliculi.  Furthermore, E. coli has been shown to induce intravascular hemolysis, and both mechanisms may result in an increased amount of bilirubin circulating in the blood.  Bilirubin can be elevated in cases of sepsis, intra-abdominal abscesses from urological, gynecological or gastroenterological origins, antiviral therapy or in patients with genetic disease such as Dubin-Johnson syndrome, Rotor's syndrome, and Gilbert's syndrome.  It has been proposed that hyperbilirubinemia is a weak marker of appendiceal perforation among persons with Gilbert's syndrome.  There exists no single diagnostic test or symptom other than surgery with pathologic examination that can definitely result in a diagnosis. Regarding the clinical use of predictors in the diagnostics of appendiceal perforation, elevated bilirubin and CRP should be considered as a supplement to other diagnostic tools such as USG and CT scans. In their study Mcgowan et al. they found that the biochemical markers (bilirubin, CRP and white cell count were significantly higher in perforation (P < 0.001). The greatest sum of sensitivity and specificity of CRP at 34.6 mg/l (sensitivity 78.57%, specificity 63.01%, and bilirubin was at 21.5 μmol/L (sensitivity 62.96%, specificity 88.31%). They concluded that Bilirubin and CRP are markers of perforation in appendicitis, but are not accurate enough to be diagnostic. 
| Conclusion|| |
Bilirubin, CRP, and ultrasound are effective for differentiation of perforated from nonperforated appendicitis. Bilirubin, CRP, and USG are important preoperative biochemical and sonographic markers of perforation, respectively in appendicitis. Thus, these three tests collectively help in early prediction of perforation and prevention of complications.
| References|| |
|1.||Konan A, Hayran M, Kýlýç YA, Karakoç D, Kaynaroðlu V. Scoring systems in the diagnosis of acute appendicitis in the elderly. Ulus Travma Acil Cerrahi Derg 2011;17:396-400. |
|2.||Escribá A, Gamell AM, Fernández Y, Quintillá JM, Cubells CL. Prospective validation of two systems of classification for the diagnosis of acute appendicitis. Pediatr Emerg Care 2011;27:165-9. |
|3.||Sand M, Bechara FG, Holland-Letz T, Sand D, Mehnert G, Mann B. Diagnostic value of hyperbilirubinemia as a predictive factor for appendiceal perforation in acute appendicitis. Am J Surg 2009;198:193-8. |
|4.||Jo YH, Kim K, Rhee JE, Kim TY, Lee JH, Kang SB, et al. The accuracy of emergency medicine and surgical residents in the diagnosis of acute appendicitis. Am J Emerg Med 2010;28:766-70. |
|5.||Doria AS. Optimizing the role of imaging in appendicitis. Pediatr Radiol 2009;39 Suppl 2:S144-8. |
|6.||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. |
|7.||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. |
|8.||Atahan K, Üreyen O, Aslan E, Deniz M, Çökmez A, Gür S, et al. Preoperative diagnostic role of hyperbilirubinaemia as a marker of appendix perforation. J Int Med Res 2011;39:609-18. |
|9.||Estrada JJ, Petrosyan M, Barnhart J, Tao M, Sohn H, Towfigh S, et al. Hyperbilirubinemia in appendicitis: A new predictor of perforation. J Gastrointest Surg 2007;11:714-8. |
|10.||Käser SA, Fankhauser G, Willi N, Maurer CA. C-reactive protein is superior to bilirubin for anticipation of perforation in acute appendicitis. Scand J Gastroenterol 2010;45:885-92. |
|11.||Borushok KF, Jeffrey RB Jr, Laing FC, Townsend RR. Sonographic diagnosis of perforation in patients with acute appendicitis. AJR Am J Roentgenol 1990;154:275-8. |
|12.||Abu-Yousef MM, Bleicher JJ, Maher JW, Urdaneta LF, Franken EA Jr, Metcalf AM. High-resolution sonography of acute appendicitis. AJR Am J Roentgenol 1987;149:53-8. |
|13.||Adams DH, Fine C, Brooks DC. High-resolution real-time ultrasonography. A new tool in the diagnosis of acute appendicitis. Am J Surg 1988;155:93-7. |
|14.||Amland PF, Skaane P, Rønningen H, Nordshus T, Solheim K. Ultrasonography and parameters of inflammation in acute appendicitis. A comparison with clinical findings. Acta Chir Scand 1989;155:185-9. |
|15.||Jeffrey RB Jr, Laing FC, Townsend RR. Acute appendicitis: Sonographic criteria based on 250 cases. Radiology 1988;167:327-9. |
|16.||Jeffrey RB Jr, Laing FC, Lewis FR. Acute appendicitis: High-resolution real-time US findings. Radiology 1987;163:11-4.16. |
|17.||Puylaert JB. Acute appendicitis: US evaluation using graded compression. Radiology 1986;158:355-60. |
|18.||Puylaert JB, Rutgers PH, Lalisang RI, de Vries BC, van der Werf SD, Dörr JP, et al. A prospective study of ultrasonography in the diagnosis of appendicitis. N Engl J Med 1987;317:666-9. |
|19.||Kang WM, Lee CH, Chou YH, Lin HJ, Lo HC, Hu SC, et al. A clinical evaluation of ultrasonography in the diagnosis of acute appendicitis. Surgery 1989;105:154-9. |
|20.||Karstrup S, Torp-Pedersen S, Roikjaer O. Ultrasonic visualisation of the inflamed appendix. Br J Radiol 1986;59:985-6. |
|21.||Lessin MS, Chan M, Catallozzi M, Gilchrist MF, Richards C, Manera L, et al. Selective use of ultrasonography for acute appendicitis in children. Am J Surg 1999;177:193-6.21. |
|22.||Takada T, Yasuda H, Uchiyama K, Hasegawa H, Shikata J. Ultrasonographic diagnosis of acute appendicitis in surgical indication. Int Surg 1986;71:9-13. |
|23.||Blumfield E, Nayak G, Srinivasan R, Muranaka MT, Blitman NM, Blumfield A, et al. Ultrasound for differentiation between perforated and nonperforated appendicitis in pediatric patients. AJR Am J Roentgenol 2013;200:957-62. |
|24.||Ozguner IF, Buyukayavuz BI, Savas MC. The influence of delay on perforation in childhood appendicitis. A retrospective analysis of 58 cases. Saudi Med J 2004;25:1232-6. |
|25.||Sisson RG, Ahlvin RC, Harlow MC. Superficial mucosal ulceration and the pathogenesis of acute appendicitis. Am J Surg 1971;122:378-80. |
|26.||Rink RD, Kaelin CR, Giammara B, Fry DE. Effects of live Escherichia coli and Bacteroides fragilis on metabolism and hepatic pO2. Circ Shock 1981;8:601-11. |
|27.||Shander A. Anemia in the critically ill. Crit Care Clin 2004;20:159-78. |
|28.||Buyukasik Y, Akman U, Buyukasik NS, Goker H, Kilicarslan A, Shorbagi AI, et al. Evidence for higher red blood cell mass in persons with unconjugated hyperbilirubinemia and Gilbert's syndrome. Am J Med Sci 2008;335:115-9. |
|29.||McGowan DR, Sims HM, Zia K, Uheba M, Shaikh IA. The value of biochemical markers in predicting a perforation in acute appendicitis. ANZ J Surg 2013;83:79-83. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]