Hyperbilirubinemia has also been found during some infective diseases involving organs other than liver.[1] Neonates are more susceptible to develop hyperbilirubinemia following gram-negative bacterial infections. Severe intra-abdominal infection in adults has also been associated with development of hyperbilirubinemia[2]. The vermiform appendix is important in surgical practice mostly due to its propensity for inflammation resulting in acute appendicitis. Worldwide acute appendicitis is the most common surgical emergency, affecting the abdomen. An emergency appendectomy is the most frequently performed abdominal operation and often it is the first major operative procedure done by a surgeon.[3] Overall lifetime risk of developing appendicitis is approximately 7% (8.6% for males & 6.7% for females) [4,5]. The male: female ratio is 1.4:1 (range is M: F = 1:1 to 3:1) [5]. The incidence of acute appendicitis is decreasing steadily since late 1940 with present incidence rate approximately up to 110 (starting from 55.3 in females & 68.8 in males) cases per 10,0000 population per year.[6]
Appendicitis commonly occurs in young adults (the highest incidence, approximately 40%, in 2nd decade of life i.e. 10-19 years and 70% of the subjects are less than 30 years old.).[7,8] Acute appendicitis is relatively rare at the extreme of age. [9,10] Most subjects with acute appendicitis present with classic signs and symptoms for the ease of diagnosis. But in some atypical presentations diagnostic confusion and delay in treatment may occur. Crohn's disease, ectopic pregnancy, diverticulitis, endometriosis, mittleschmerz, mesenteric adenitis, omental torsion, pelvic inflammatory diseases, ruptured ovarian cyst, urinary tract infection may mimic acute appendicitis. Worldwide mean value for difference in diagnostic error rate, ranges from 12% to 23% and 24%–42% respectively in men and women. Error occurs mostly in whites (74%), while it is lesser in darker complexions (5%).[9]
Surgical delay in a prompt management of the subjects with appendicitis (not with perforation, in particular), either due to delay in presentation (particularly in males with retrocaecal or retroileal position) or misjudgment, leads to dread complications like gangrenous changes and perforation of the appendix. Gangrene or perforation further leads to more complications like appendicular abscess formations, localized/generalized peritonitis, fecal fistula formation, intestinal obstruction due to adhesion formation, portal pyemia, sepsis and sterility in women of child-bearing age (though recent studies denies it as a major risk factor) with overall increased morbidity & prolonged hospital stay[5,11]. In adults, the incidence of appendicular perforation is 13% - 37%.[12] The risk is higher in extreme of ages (45% in under 5 years age group and 51% in over 65 years age group).[7,10] The mortality rate for uncomplicated, non-perforated appendicitis is 0.1-0.5% while that of perforated appendicitis is much higher, ranging from 3% overall to as high as 15% in elderly subjects.[7]On the contrary, in case of diagnostic difficulties and atypical presentations if appendectomy is performed based on clinical suspicion only, may increase the number of unnecessary appendectomies (up to 20%). [13] The rate of negative appendectomy (mostly due to pelvic inflammatory conditions) is 35 to 45% in women of child bearing age.[14] Unnecessary appendectomy caries a small risk of wound sepsis and the subsequent adhesive intestinal obstruction and occurrence of incisional hernia.
In spite of numerous advances in the diagnosis, evolved in the last 125 years, still now acute appendicitis continues to be a diagnostic challenge for surgeons and it remains mostly a clinical Diagnosis. Additional laboratory tests ,scoring systems, Ultrasonography (sensitivity of 0.86 & specificity of 0.81 in experienced hand), Multi Detector computed tomography (MDCT, with sensitivity & specificity of 0.94 & 0.95 respectively) , scintigraphy, Magnetic Resonance Imaging(specially in pregnancy) and diagnostic laparoscopy has been used which may support the primary clinical assessment to reach the diagnosis.[15,16,17,18]
Several diagnostic scoring systems such as the Alvarado score (Scale 0-10), modified Alvarado score, Pediatric Appendicitis Score (PAS; scale 0-10), Rajalsteri Pengiran Anak Saleha Appendicitis(RIPASA) score for use in Asian patients(Scale 0-14), and Appendicitis Inflammatory Response Score (AIRS; scale 0-12) are commonly used in clinically suspected cases.[16,19-22] But these scoring systems do not assess the risk of complications like appendicular gangrene or perforation. None of the above mentioned scores use hyperbilirubinemia as a marker.Some studies had showed that risk of appendicular perforation increases three times in subjects with total serum bilirubin levels more than 1 mg/dl.[9]
Obstruction of appendix lumen, forming a closed loop, either by fecolith or mucosal edema is the major cause of pathological changes in acute appendicitis. Fecolith increases the severity of appendicitis, like 40% of uncomplicated, 65% of Gangrenous Appendicitis and 90% of Perforative Appendicitis has been found to be associated with presence of fecolith.[23,24]Appendix perforation occurs mostly distal to the point of luminal obstruction along the anti -mesenteric border. The appendix perforates about 12 to 48 hours after the onset of acute appendicitis and is accompanied by an abscess cavity walled off by the small intestine and the omentum. Rarely free pertoration of the appendix into the peritoneal cavity occurs, which may be accompanied by peritonitis and septic shock and may be complicated by subsequent formation of multiple intraperitoneal abscesses.
Wangensteen, postulated that mucosal folds and a sphincter like orientation of the muscle Fibres at the appendiceal orifice makes the appendix susceptible to obstruction. He proposed sequence of events to explain appendicitis as depicted in [Figure 1].[9] The flora of the inflamed appendix contains more bacterial load (anaerobes in 60% cases, peptostreptococcus ,pseudomonas,bacteroides splanchnicus/intermedius, lactobacillus) than usual species in normal appendicitis[25] . Fusobacterium necrophorum /nucleatum, which is absent in normal situation, have been identified in 62% of inflamed appendices.[26] Bacteroides fragilis and Escherichia coli are the most frequently isolated bacteria in appendicitis[27]. Nearly 80% of blood supply to the liver comes from portal venous system, which carries absorbed substances including bacteria and toxins from intestine. Normally, small amount of bacteria and their toxic products get cleared after entering liver by detoxification and immunological action of reticulo-endothelial system. But kupffer cells may fail to clear the over abundant bacterial load in case of complicated acute appendicitis which in turn damage hepatocytes and rise serum bilirubin level. When there is bacteraemia, it leads to endotoxemia with resultant impaired excretion of bilirubin from the bile canaliculi.[27] Cytokines e.g interleukin-6(IL6), tumor necrosis factors (TNF) are also been considered to depress excretory functions of the liver resulting in hyperbilirubinemia without rise in liver enzymes level.[28]
Aim of the present study is to evaluate the diagnostic role and predictive value of elevated total serum bilirubin level as a diagnostic parameter of complicated (gangrenous or perforated) appendicitis. Whether direct bilirubin, indirect bilirubin or both is increased in case of complicated appendicitis and their relation with complicated appendicitis were also studied.The relationship of other patient related parameters with complicated appendicitis were also evaluated in the present study.