European Journal of Cardiovascular Medicine

Acute appendicitis, a common surgical condition, has a lifetime risk of needing an appendectomy estimated at 12% for men and 23% for women.¹ The significance of early detection and proper management of appendicitis has become more evident over time. Despite the expertise of surgeons, the misdiagnosis rate of appendicitis remains at 15.3%.² Diagnosing appendicular pathologies primarily relies on clinical evaluation. Most appendicitis cases are straightforward but can be difficult to distinguish from a perforated appendix, especially in elderly patients and young children. Between 18.3% and 34.0% of appendicitis cases are complicated by perforation.^{3, 4}

Simple acute appendicitis can often be treated with a relatively minor surgery, an appendectomy, leading to a quick recovery with few complications. However, delayed diagnosis and subsequent perforation can lead to life-threatening conditions.⁵ The development of additional diagnostic tools beyond clinical examination and imaging could improve early detection. Recent studies suggest that elevated bilirubin levels are linked to both acute appendicitis and appendicular perforation. The mortality rate for uncomplicated appendicitis is about 0.3%, but rises to 6% for cases complicated with a perforation.⁶ Diagnosing perforated appendicitis relies on clinical examination, along with elevated inflammatory and biochemical markers. Early identification of perforation is crucial to control sepsis and improve outcomes, as it helps surgeons prepare for a more complex procedure.⁷ Recent surgical literature^{8, 9, 10} has revived interest in using biomarkers to aid clinical diagnosis, with studies and meta-analyses indicating that serum bilirubin levels may help differentiate between simple acute appendicitis and a perforated or gangrenous appendix.

Hyperbilirubinemia results from an imbalance between bilirubin production and excretion by the liver. Portal blood, which carries nutrients and substances from the gut, including bacteria and toxins, is typically cleared through the liver’s detoxification and immune mechanisms. When bacterial load overwhelms the liver's defences, it may impair hepatocyte function, leading to an increase in serum bilirubin levels, either alone or with elevated liver enzymes, depending on the lesion's type, severity, and location.¹¹ Jaundice associated with sepsis is well-known and often linked to gram-negative bacteria.¹²

Hyperbilirubinemia can serve as a useful diagnostic tool for identifying a perforated appendix. Elevated serum bilirubin levels may aid in the early diagnosis of acute appendicitis and in predicting its complications, particularly perforation.¹³ Other blood markers, such as C-reactive protein (CRP) and white blood cell (WBC) count, can also be elevated in both acute and perforated appendicitis.¹⁴

Therefore, this study aims to evaluate the role of pre-operative hyperbilirubinemia as a predictor of complicated appendicitis.This would help us have a better understanding of the patient’s condition before surgery and be better prepared for the anticipated outcomes.

AIM AND OBJECTIVES AIM

To evaluate the role of pre-operative hyperbilirubinemia in the prediction of complicated appendicitis.

OBJECTIVES

To evaluate the association of pre-operative hyperbilirubinemia in the prediction of appendicular perforation.

 To analyze the sensitivity, specificity, positive predictive value and negative predictive value of pre-operative hyperbilirubinemia in acute appendicitis

This prospective observational study was conducted in Department of General Surgery at Pt. B. D. Sharma Post graduate Institute of Medical Sciences, Rohtak. This study was performed in 71 patients who were underwent emergency appendectomy from June 2021 to December 2022.   Patients were admitted with features of acute appendicitis or suspected appendicular perforation in the emergency were included in this study. The criteria for the selection of cases was based on clinical history, physical findings, radiological study, haematological, and biochemical investigations.

INCLUSION CRITERIA

 All patients with clinically diagnosed acute appendicitis or suspected appendicular perforation on admission and were underwent appendicectomy were included in this study.

EXCLUSION CRITERIA

 Patients who were documented to have a past history of liver disease, positive for hepatitis B virus surface antigen (HBsAg), HCV, cholelithiasis, a malignancy of the hepatobiliary system, jaundice, chronic alcoholism, hemolytic disease, congenital or acquired biliary disease, and drug intake causing cholestasis were excluded from this study.

Patients  who were less than 15 years of age   and who did not given consent for surgery were also  excluded from the study.

PROCEDURE

Patients who were diagnosed with acute appendicitis or suspected appendicular perforation after all the relevant investigations were admitted and were underwent appendicectomy. Data was collected from all patients included in the study and entered in a pre-specified proforma at admission and serially after that. Demographics details (age, gender), pre-operative investigations including complete blood count, tests for liver function (serum total bilirubin: direct, indirect), urea and creatinine, random blood sugar, HIV, HbsAg, and hepatitis C antibody (anti-HCV), imaging (ultrasonography), and will be recorded. The normal bilirubin range in adults will be taken as direct bilirubin 0–0.2 mg%, indirect bilirubin 0.2–0.7 mg%, and total bilirubin 0.3-1.0 mg%. Patients who were diagnosed clinically, aided by imaging studies, and were taken up for emergency appendicectomy. Intra operative findings with respect to appendix were recorded and specimen was sent for histopathological examination. The post-operative biopsy results were used to correlate the intra operative findings of appendicular perforation. Pre-operative hyperbilirubinemia when noted was correlated with the intra operative findings of acute appendicitis and other complicated appendicitis which include appendicular perforation and gangrenous appendix.

MEASUREMENT OF OUTCOME

• Serum Bilirubin (mg/dl)-total, direct and indirect
• Histopathology report-acute appendicitis and appendicular perforation

STATISTICAL ANALYSIS

All the collected data was entered in Microsoft excel spreadsheet. Descriptive statistics were analyzed with SPSS software. Continuous variables are presented as mean ± SD. Categorical variables are expressed as frequencies and percentages. Paired T test was used for evaluating paired variables for quantitative date. Chi-square test was used for qualitative data whenever two or more groups were used to be compared. Level of significance was set at p≤0.05.

The present prospective observational study was conducted on 71 patients who were clinically diagnosed with acute appendicitis or suspected appendicular perforation and underwent emergency appendectomy.  There were 50 males and 21 females with the male to female ratio being 2.38:1. Majority of the patients in the present study were males (70.4%).The age of patients ranged from 15-68 years. Maximum number of patients (62%) who underwent appendectomies were from 15-30 years of age group. The mean age of the included patients was 30.07±13.54 years.  There were 48 cases of acute appendicitis and 23 cases of appendicular perforation/gangrene. In the patients of acute appendicitis, 31 out of 48 patients belonged to the age group of 11-30 years. In the patients of appendicular perforation 13 out of 23 patients belonged to the age group of 11-30 years as well. Out of 50 males, 34 had acute appendicitis and 16 had appendicular perforation/gangrene. And out of 21 females, 14 had acute appendicitis and 7 had appendicular perforation/gangrene.

 In the patients with acute uncomplicated appendicitis, around 82% had normal serum total bilirubin levels pre-operatively whereas only 18% of these patients had hyperbilirubinemia.

On the other hand, in the patients of complicated appendicitis around 82% had raised serum total bilirubin levels in the pre-operative period. The mean total serum bilirubin level of all 71 patients in our study was found to be 0.909±0.505 mg/dl which was slightly towards the higher side of the normal values (<1.0 mg/dl). The mean of total serum bilirubin in acute appendicitis was 0.693±0.338 mg/dl. The mean total serum bilirubin in perforated or gangrenous appendicitis was 1.360±0.502 mg/dl which was above the normal range indicating hyperbilirubinemia. The mean direct and indirect bilirubin in patients diagnosed with acute appendicitis was 0.175±0.127 mg/dL and 0.518±0.288 respectively. Similarly, mean direct and indirect bilirubin in patients diagnosed with appendicular perforation was 0.291±0.147 mg/dL and 1.069±0.393 mg/dL respectively. Among the patients of appendicular perforation/gangrene, the mean serum bilirubin among males was 1.425±0.52 mg/dl in comparison to 1.2±0.43 mg/dl among females.

Among the group of 48 patients with acute appendicitis, only 4 patients had raised serum total bilirubin levels and the rest 44 had normal level of total serum bilirubin. On the other hand, among the 23 patients of appendicular perforation/gangrene, 18 patients had serum hyperbilirubinemia pre-operatively and only 5 patients had normal serum total bilirubin levels.

In our study population of patients undergoing emergency appendicectomy, appendicular perforation/gangrene as identified on histopathology was considered as a case of complicated appendicitis. The cut off for serum total bilirubin to be considered as raised was taken as >1mg/dl. The sensitivity and specificity of serum bilirubin as a diagnostic predictor of appendicular perforation was found to be 69.5% and 87.5% respectively. The positive predictive value and negative predictive value was found to be 72.3% and 85.9% respectively. The diagnostic accuracy of this test was found to be 81.7% with 95% confidence intervals.

Acute appendicitis remains the most common acute surgical condition of the abdomen. Appendectomy is the most performed emergency procedure for acute appendicitis in the world. Acute appendicitis is diagnosed essentially by clinical examination. It is often difficult to reach a proper diagnosis as classical signs and symptoms suggesting acute appendicitis may not be present in all. Different presenting symptoms and clinical signs always mimic the diagnosis of acute appendicitis, especially in women.¹⁵ Multiple biochemical tests have been used to fill in the gaps with clinical examination including serum bilirubin. In our study the age of patients ranged from 15-68 years. Maximum number of patients (36.6%) who underwent appendicectomies were from 20-30 years of age group. The mean age of the included patients was 30.07±13.54 years. (Table-1) This was comparable to other studies. Chaudhary et al found that 48% of their study population was between 15-24 years age group and the mean age was 29.27 years.¹⁶

Ramu et al also found 44.7% of their study population between 21-30 years with the mean age being 27.80 years.¹⁷   Kumar et al also found 39.79% of their study population in the age group of 21-30 years and mean age is28.07.¹⁸

Table 1- Demographic Data

 Table -2    Correlation of Serum Bilirubin and Histopathology Findings

In our study population, of the patients of acute appendicitis 87.5% had normal serum bilirubin levels and only 12.5% had elevated serum total bilirubin levels. Among the patients of appendicular perforation around 69.57% had serum hyperbilirubinemia and 30.43% had normal serum bilirubin levels. (TABLE-2)      Rekhi et al found serum hyperbilirubinemia in 42% and 50% of acute appendicitis cases and appendicular perforation patients.¹⁹ Ramu et al found that 29% of patients of acute appendicitis had serum hyperbilirubinemia whereas 89% of patients of appendicular perforation had serum hyperbilirubinemia.¹⁷

In the study by Kumar et al among the patients with diagnosis of acute appendicitis only 33% had raised serum bilirubin levels whereas among those with perforated appendix, 63% had raised serum bilirubin levels comparable to the results of our study.¹⁸   Both these studies suggested that hyperbilirubinemia was more commonly associated with appendicular perforation than with acute appendicitis. In the study by Vineed et al serum hyperbilirubinemia was present in 87% and 34% of simple acute appendicitis and appendicular perforation respectively.²⁰

This contrasted with the other studies as serum hyperbilirubinemia was more commonly seen in simple acute appendicitis than in the cases of perforated appendix. It has been suggested that a raised bilirubin is indicative of complicated, perforated appendicitis.^21-22

Bilirubin is felt to rise as a response to intra-abdominal infection causing a transiently portal pyrexia and resulting inflammatory-mediated cholestasis.²³ There have been several reports of hyperbilirubinaemia in appendicitis.^24-25

Estrada et al hypothesised that hyper- bilirubinaemia may be associated with appendiceal perforation and showed that more patients with a perforated or gangre nous appendix had hyperbilirubinaemia than those with simple acute appendicitis.¹³

Table 3 - Sensitivity, Specificty, Positive Predictive Value And Negative Predictive Value Of Serum Total Bilirubin As An Indicator For Identifying Patients With Appendicular Perforation Among Patients Of Acute Appendicitis

We studied the sensitivity, specificity, positive predictive value, and negative predictive value for the total serum bilirubin as a test for predicting perforated appendix. The sensitivity and specificity of serum bilirubin as a marker in predicting appendicular perforation was 72.7% and 85.7% respectively. Similarly, the negative predictive value and positive predictive value for the test is 87% and 69.5% respectively. (TABLE 3)  Comparable results were found in the studies illustrated in the table above. Marimuthu et al taken cut off of total bilirubin >1 mg/dl with negative predictive value 92.15%, positive predictive value 28.72% sensitivity 72.15% specificity 71% and p-value is <0.001.²⁶ Ramu et al showed that hyperbilirubinemia with a cut-off point of >1.3 mg% for appendicular perforations has a sensitivity of 80%, a specificity of 89%, a positive predictive value of 93%, and a negative predictive value of 96%. They found that by combining the clinical diagnosis and bilirubin levels (cut-off 1.3 mg%), the detection rate of appendicular perforation rises from 82% to 97%, which is very significant.¹⁷ McGowan et al found that the sensitivity and specificity of bilirubin was at 1.2mg/dL (sensitivity 62.96%, specificity 88.31%).²⁷    Atahan et al found the specificity of high bilirubin levels for perforated appendicitis was 87.21%. They concluded that total bilirubin level could be used in the early diagnosis of perforated appendicitis.²⁸ Sand et al found a high negative

predictive value of 93% and a specificity of 86%. They described the odds of appendicular perforation to be 3 times higher for patients with hyperbilirubinemia compared with those with normal bilirubin levels.⁶ 

Hence, we have seen that patients with appendicular perforation had higher levels of bilirubin as compared to that of acute appendicitis. So, we inferred that patient with

features suggestive of appendicitis with raised levels of serum total bilirubin, were more susceptible of having appendicular perforation than those with normal levels of total serum bilirubin. Because no one clinical or laboratory test can accurately predict appendicular perforation, serum bilirubin levels are obtained upon admission and combined with the history, clinical examination, laboratory, and radiographic tests to establish the diagnosis and determine suitable care.

Conflicts of Interest—Nil

Source of support—Nil

Acknowledgement—All the authors contributed well in preparing this article for publication in form of writing, editing and conceptualization.

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