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ORIGINAL CONTRIBUTIONS

Received: April 24^th 2015

Accepted: July 13^th 2015

Hyperbilirrubinemia as a predictive factor of perforated appendicitis

Bianca Alanis-Rivera,^a Luis Abraham Zúñiga-Vázquez,^b María del Carmen Silva-Escamilla^a

^aDepartamento de Epidemiología, Unidad de Medicina Familiar 29, Instituto Mexicano del Seguro Social, Ciudad de México, México

^bDepartamento de Cirugía General, Hospital General “Rubén Leñero”, Secretaría de Salud del Distrito Federal, Ciudad de México, México

Communication with: Bianca Alanis-Rivera

Telephone: (55) 5771 3933

Email: biancalanis@hotmail.com

Background: Recent studies considered hyperbilirubinemia as a marker to identify the presence of perforated appendix. The aim of the study is to verify that the presence of hyperbilirubinemia is a useful marker to identify the presence of perforated appendix before surgery, and thereby, provide early treatment to avoid progression of the disease and its complications.

Methods: This is a retrospective study, which identified 225 patients, who met the inclusion and exclusion criteria, from January 2012 to October 2014 at the IMSS General Hospital 29, taking into account laboratory results and postoperative, performing a univariate, bivariate and multivariate analysis.

Results: 56.9% showed bilirubin < 1, from which 16.4% presented perforation, while 43.1% showed bilirubin > 1, 62.88% presented perforated appendicitis. Hyperbilirubinemia increases 17 times the risk of perforated appendix (RMP: 17.63; IC 95%: 6.882-45.207; p < 0.001) which is statistically significant.

Conclusions: Considering the limitations of this study, it can be inferred that hyperbilirubinemia is present in a great number of patients with perforated appendicitis, so it could be considered a relevant laboratory test to include within the protocol of appendicitis, which in turn, may determine a better planning for the surgical approach.

Keywords: Hyperbilirubinemia; Appendix; Appendicitis

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Acute appendicitis (AA) is an inflammation of the cecal or vermiform appendix, which begins with obstruction of the appendiceal lumen, resulting in increased intraluminal pressure and risk of perforation.

The importance of acute appendicitis is that it is considered the most frequent cause of emergency abdominal surgery worldwide,¹ with a prevalence in our country of 47.79% of emergency surgical diseases² and an incidence of 1.5 to 1.9 per 1000 inhabitants;³ over 250,000 cases are diagnosed annually and operated on in the United States.⁴ It occurs more often in men than in women, with a lifetime risk of 8.6 and 6.7% respectively.⁵ Most of the affected population is between 25 to 35 years old.⁶

Negative appendectomies present from 5 to 40%, and in other cases the suggestive presence of perforated appendicitis (PA) has a late intervention in 5 to 30%,⁷ which causes, in turn, an increase in mortality from 0.3% in acute appendicitis to 6.5% in perforated appendicitis.⁸

PA involves multiple complications that can endanger life, such as a surgical wound infection (8-15%), perforation (5-40%), abscesses (2-6%), sepsis and death (0.5-5%).⁹

The pathophysiology described by Fitz¹⁰ suggests that once appendicitis is established, perforation is only a matter of time.

The diagnosis of acute appendicitis is based primarily on clinical findings, which are difficult to identify and correlate with acute appendicitis, especially during the early hours of clinical signs.¹¹ Add to this the difficulty of clinically differentiating non-perforated acute appendicitis from perforated appendicitis, especially in elderly patients or children.¹²

Early diagnosis or identification of complications in the patient with acute abdomen is the challenge we face, although there have been advances in diagnostic laboratory and imaging techniques.¹³

Recent studies have suggested that bilirubin levels are associated with the presence of perforated or gangrenous appendicitis.¹⁴ A biochemical test, like bilirubin level, may be useful in conjunction with clinical findings to decide which patients are likely to have complicated appendicitis and should be considered for immediate surgery.¹⁵

Hyperbilirubinemia is the result of an imbalance between bilirubin production and excretion by the liver. The liver receives blood mainly through the portal venous system, from the abdominal organs; in a small percentage, even in healthy people, bacteria are found in the portal blood, which are eliminated by detoxification and immune action of the reticuloendothelial system (RES) of the liver, which acts as a first line of defense in cleaning toxic substances, bacteria, and their products; but when the bacterial load exceeds the function of the Kupffer cells, it may cause dysfunction or damage reflected in increased serum bilirubin (SB), alone or in combination with liver enzymes depending on the type, severity, and location of the injury. Recently, other substances known as cytokines, e.g., IL-6, tumor necrosis factor (TNF), have also been marked as responsible for the decreased excretion of bilirubin and may cause an increase in the level of SB and no increase in liver enzymes.¹⁶

Several studies have shown that portal pyaemia can follow a terminal bowel infection resulting in portal phlebitis or septic emboli.¹⁷ Ischemia due to decreased portal blood flow to the liver is the mechanism of liver injury. In both cases, beyond liver injury, this leads to dysfunction of the hepatocytes and tubule, leading to a mixed type of hyperbilirubinemia (hepatocellular and intrahepatic cholestasis).¹⁸ It can also be related to the cholestatic effect of the endotoxin acting on the Na/K ATPase. All components of bile show a higher level in the serum. The conjugation of bile is intact, but excretion is defective.¹⁹

Determining the algorithm for diagnosing PA would allow us to reduce the frequency of complications and the number of operations secondary to complications, and could contribute significantly to reducing costs and hospital stay.

Methods

This study was conducted in the Hospital General de Zona con Unidad de Medicina Familiar 29. The type of study was observational, cross-sectional, retrospective, and comparative, including all records of patients from January 2012 to October 2014 who had bilirubin levels previous to surgery and who were diagnosed with acute appendicitis. The study excluded patients with a personal history of diseases that include or cause elevated bilirubin, such as: alcoholism, promiscuity, sexually transmitted diseases, intravenous drug use, previous transfusions, tattoos, organ transplants, previous hepatitis, cholestatic drugs, cancer, jaundice, cholelithiasis, hemolytic disease, pancreatitis, Crigler-Najjar syndrome, Gilbert's syndrome, Dubin-Johnson syndrome, Rotor syndrome, systemic lupus erythematosus, as well as records lacking postsurgical diagnosis; patients with postoperative diagnoses of reactive appendicitis or diagnoses not corresponding to appendiceal disease were eliminated from the study.

The concept of perforated appendicitis was taken as the continuum reported by the surgeon in postsurgical notes. Hyperbilirubinemia was considered any level ≥ 1 mg/dL. Age was classified into 5 groups for univariate analysis, however for further analysis it is classified into over 60 and under 60. The onset of symptoms is taken as a cutoff for more than 48 hours or less than 48 hours of evolution.

Ethical aspects

This study was carried out under the ethical consideration in the Ley General de Salud, in its second title: "On the ethical aspects of research on human beings," which categorized this research as without risk, since retrospective documentary techniques and research methods are used, and no intervention or intentional modification was made to the physiological, psychological, and social variables of individuals participating in the study, including those such as: questionnaires, interviews, review of records, and others. This releases the investigator from obtaining informed consent.

Statistics

The collection of information was submitted to review and coding, data capture, and analysis using SPSS version 22.

The variables were considered qualitative, and were expressed as absolute and relative frequencies; in the same way, with quantitative variables, measures of central tendency and dispersion measures, non-normal distribution, as well as specific prevalence with 95% confidence intervals were used. Data were analyzed using the Kolmogorov-Smirnov test, finding an asymptotic significance of < 0.05, so nonparametric tests were used. In comparing continuous independent variables in the groups with or without perforation, Mann-Whitney U was applied for lack of normal distribution.

Pearson’s Chi-squared, Mantel-Haenszel Chi-squared, and ANOVA were used for the analysis of differences in proportions, the association, and the magnitude of the association between nominal independent variables with respect to groups reported with and without hyperbilirubinemia; it is worth mentioning that Fisher's exact test was applied in the case of lower values ​​than expected.

Using bivariate analysis, independent variables were selected that were significantly associated with the presence of perforated appendicitis.

The binary logistic regression model was used for perforated appendicitis, which included the factors: bilirubin level, fever, leukocytosis, and days of hospital stay, adjusted for age and gender.

Results

A total of 1197 patients were found who underwent surgery for acute appendicitis, 29.65% of which (355) were performed in 2012; 39.93% (478) during 2013, and 30.46% (364) through October 2014. 225 patients were studied, over 18 years of age with a diagnosis of acute appendicitis in the General Surgery department; 63.6% of them had perforated appendicitis, with a frequency of Phase IV appendicitis of 36.4% (Table I). The median age was 34 years, with an interquartile range of 74 (Table II). The highest prevalence of appendicitis and perforated appendicitis was identified in the 18-29 age group, with a rate of 40.4% (91) and a prevalence of 12.44% (95% CI: 11.02-20.37). Regarding gender, 127 men (56.4%) had appendicitis, of which 21.33% (95% CI: 16.49-27.14) had perforated appendicitis (Table III). The median onset of symptoms was 2 days; in those with more than 48 hours of evolution, 22.7% (95% CI: 17.68-28.57) were perforated. In people who had AA, median bilirubin level was 0.9 g/dL; hyperbilirubinemia in patients with PA was 27.1% (95% CI: 21.72-33.27) (Table IV).  

No difference was observed between men and women with perforated appendicitis, since an odds ratio of prevalence (ORP) of 1.14 was obtained (95% CI: 0.66-1.98); also, with regard to age over 60 years (ORP: 0.447; 95% CI: 0.201-0.993). 

Hyperbilirubinemia increased the risk of PA by almost nine times (ORP 8.63, 95% CI: 4.62-16.10) than in those with normal levels. In patients with more than 48 hours of evolution, the risk of PA was 6.46 times higher (95% CI: 3.53-11.83). Regarding leukocytosis levels, no significant difference between groups was presented (ORP: 1.23; 95% CI: 0.553-2.77). (Table V) PA patients showed 50% longer hospital stays. When performing multivariate analysis, the most important variable was the presence of hyperbilirubinemia, which brought 17 times higher risk compared to those with normal levels of bilirubin (ORP: 17.63, 95% CI: 6.882-45.207; p < 0.001); women had 2.6 times the risk of PA (ORP: 2.6, 95% CI: 1.071-6.334), and patients with greater delay in diagnosis had a 4.39 times increased risk (95% CI: 1.927-10.0) (Table VI).

As regards hyperbilirubinemia, a sensitivity of 74.34% and specificity of 74.82% was obtained, compared with leukocytosis with 87 and 85% respectively, with an area under the curve of 0.785 for hyperbilirubinemia and 0.519 for leukocytosis (Figures 1 and 2). Likewise, the positive predictive value was 62.8% for hyperbilirubinemia and 37.1 for leukocytosis (Table VII).

Discussion

An observational study was presented that represented the prevalence of perforated appendicitis in patients who had hyperbilirubinemia in the Hospital General de Zona 29.

Cases of acute appendicitis at HGZ 29 found a prevalence of appendicitis of 35%, which was the main cause of surgery, which correlates with that published by Varadhan et al.,¹ who report this condition as the most frequent cause for surgery worldwide. The highest prevalence was observed in patients between 18 and 39 years old with 39%, which is consistent with reports by Yahya A. Al-Abed²⁰ and Young Ran Hong et al.^21,22 who mentioning ages 25-35 as the most affected population.

As for the gender difference, we found differences with reports from other authors¹¹ that the highest prevalence was obtained in men. This could be explained because the majority of the population in this unit is female. Consistency was found with reports by Kearney et al.²³ on the importance of the period of time between the onset of illness and medical care, as there was a higher prevalence of perforated appendicitis in a clinical picture with more than 48 hours of evolution (22.7%), compared with less elapsed time (13.8%).^24,25 Similarly, the risk of perforation is minimal within the first 24 hours of onset of symptoms, and increases with the passage of days, as reported by Temple et al.^26,27 which correlates with the findings in this study, since patients with less than 48 hours of evolution showed lower frequency of perforated appendicitis (21.42%).

This study identified a median of 0.9 mg/dL in the bilirubin level, compared with the results of Sand et al.^28,29 who scored an average of 0.9 mg/dL and a mean of 0.7 mg/dL, with a prevalence of 27.1% for those with perforated appendicitis, similar to that found by Young Ran Hong^30,31 with 29.38%. Furthermore, bilirubin is mentioned with a specificity of 86%, similar to that reported by Burcharth and Emanuel,^32-34 which is higher for identifying appendiceal perforation compared to leukocyte count (55%), similar to what was said by Pangiotopoulou and Hany Noh,^35,36 and PCR; however, in our study it was higher for leukocytosis. 

Some studies show that levels of bilirubin can be considered a preoperative diagnosis in patients with acute appendicitis, as it has high sensitivity and specificity for perforated appendicitis. In the study by Athan³⁷ that retrospectively studied a total of 453 patients undergoing surgery with the diagnosis of acute appendicitis, it was observed that elevated levels of total bilirubin can help discriminate between suppurative appendicitis and perforated appendicitis; like Khan,³⁸ who demonstrated the presence of hyperbilirubinemia with a prospective study in 45 patients, which can be considered a diagnostic method for acute appendicitis. However, our results regarding sensitivity and specificity should be considered with caution, considering how patients were selected.

Finally, the variable that we identified with the greatest relevance was the presence of hyperbilirubinemia, with 17 times greater risk of appendiceal perforation; therefore we consider the presurgical presence of hyperbilirubinemia in patients diagnosed with acute appendicitis.

Conclusions

Appendicitis is a condition of relevance to hospitals, since it is the leading cause of surgical emergency locally and globally.

Considering the limitations of this study, we can infer that hyperbilirubinemia is present in most patients with perforated appendicitis, so it could be seen as a relevant laboratory test to include in the diagnostic protocol for perforated appendicitis, which, in turn, can help better planning for surgical approach and shorter waits in the emergency room, thus reducing the risk of complications.

We could infer that the increase in the presence of patients with perforated appendicitis may be due to the use of painkillers and antibiotics without prescription, because primary care physicians may have made a wrong diagnosis because, at the ends of life, appendicitis presents more atypical clinical data, deterring diagnosis and increasing the risk of disease progression.

It is important to make timely and proper diagnosis of perforated appendicitis, as this increases the time of hospital stay secondary to peritonitis, abdominal sepsis, abscess, stercoral fistula, and mortality, further increasing costs/day/bed, so it is important to emphasize diagnosis of patients with perforated appendicitis, using some clues for suspicion, such as the presence of hyperbilirubinemia. However, studies should continue that contribute more information on the results so far obtained, which could improve patient selection, and which will have support to achieve the gold standard for this condition.

Acknowledgments

We thank the Hospital General de Zona con Unidad de Medicina Familiar 29 of the Instituto Mexicano del Seguro Social for the facilities to provide the records and facilities for this study.

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