Article, Surgery

Ischemia-modified albumin as a predictor of the severity of acute appendicitis

a b s t r a c t

Background: The Early prediction of gangrenous/Perforated appendicitis is of great importance for the surgical planning, further treatments, and predicting the course of disease. ischemia-modified albumin was previously reported as a biomarker of various ischemia-basED diseases. Our aim is to determine the predictive value of serum IMA in the severity of acute appendicitis. Methods: Sixty-two patients who underwent urgent appendectomy were included in the study. Plasma level of IMA was measured after diagnosis and before treatment. All patients were classified as noncomplicated (acute) appendicitis and complicated (gangrenous/ perforated) appendicitis according to histoPathological findings, and comparisons were made between the groups. Results: The data of 62 patients with a mean age of 30.1 years were statistically evaluated. The pathological diagnoses were acute appendicitis in 33 (53.2%), and gangrenous/perforated appendicitis in 29 (46.8%) patients. There were significant differences in computed tomography findings (P = .031) and IMA (P = .012) levels between the groups. A strong positive correlation between IMA levels and CT findings was also found (Spearman ? = +0.688, P = .003). Conclusions: The IMA can be considered as a novel and useful marker to distinguish gangrenous/perforated appendicitis from noncomplicated appendicitis. The correlation of IMA with CT findings also enhances the predictive value of IMA.

Introduction

Acute appendicitis is one the most common causes of acute ab- domen syndrome requiring emergent surgical intervention. Gangrene and perforation are among the dangerous complications of AA, with a ratio of up to 40% in all cases with AA [1]. However, clinical symptoms, physical examination findings, and radiological characteristics are non- specific to determine the extent of disease, particularly appendicial per- foration. Additionally, radiological tests have high costs, and carry a radiation exposure especially in pediatric population. To date, several biochemical markers such as white blood cell count , C-reactive protein, procalcitonin, and total bilirubin were reported as potential predictors of complicated appendicitis [2-5]. However, none of those were found to be able to reliably predict appendiceal perforation and are not widely used clinically.

? This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

* Corresponding author at: Department of General Surgery, Numune Training and Research Hospital, Talatpasa bulvari no: 5, Altindag, Ankara, Turkey. Tel.: +90 5053573122 (mobile).

E-mail address: [email protected] (M.O. Kilic).

Ischemia-modified albumin is a well-known biomarker of ischemia-based diseases such as stroke, Acute mesenteric ischemia, and acute coronary syndrome [6-8]. It has been also reported as an indi- cator of oxidative stress condition that is considered to play an impor- tant role in the pathogenesis of AA [9]. Although different cut-off values of IMA have been reported for various ischemic diseases, serum levels higher than 0.400 absorbans unit (ABSU) are generally accepted as a sign of ischemia [10].

Goal of this investigation

In this study, we aimed to determine whether serum IMA can be used as a novel indicator of appendicial perforation.

Methods

Patients and study design

Sixty-two patients who were operated on emergently for AA in a tertiary reference hospital between January 2016 and May 2016 were included in this prospective clinical study. The study was performed in

http://dx.doi.org/10.1016/j.ajem.2016.10.010

M.O. Kilic et al. / American Journal of Emergency Medicine 35 (2017) 92-95 93

accordance with the guidelines of the Declaration of Helsinki, and written informed consent was obtained from all patients before partici- pating in the study.

Table 2

The comparison of demographic, clinical, and radiological characteristics between the 2 groups

Patients with diabetes mellitus, chronic renal/hepatic failure and cirrhosis, and those younger than 18 years old were excluded from the study. Demographic, clinical, laboratory, and radiographic information was collected including age, gender, WBC, sonographic and tomographic findings, type of surgery (open or laparoscopic appendectomy), and hospital stay were recorded. Leukocytosis was defined as a WBC level greater than 10.0 x 10³/uL. Plasma level of IMA was measured after diag- nosis and before treatment of AP. Albumin cobalt binding calorimetric assay, previously described by Bar-Or et al. [10], was used for the mea- surement of IMA, and the results were given in absorbans unit (ABSU). A formula (individual serum albumin concentration/median serum albumin concentration of the population) x IMA ABSU value was used to eliminate the effect of albumin on IMA, and hence to obtain the corrected IMA [11].

Sonographic and tomographic evaluations were made by 2 radiolo-

gists (with expertise in the field of emergency abdominal diseases) in the emergency department. Appendiceal maximal diameter, thickness of appendiceal wall, periappendiceal fat infiltration, appendicolitis, periappendicular abscess, and ascites were the abdominal CT findings of perforation [4,12,13].

Characteristics Acute appendicitis (n = 33)

Gangrenous/perforated P

appendicitis (n = 29)

The patients were categorized into two groups according to the histo- pathological results of excised appendices: non-complicated (acute) ap- pendicitis and complicated (perforated and/or gangrenous) appendicitis.

Statistical analysis

Statistical analyses were performed using SPSS 17.0 (SPSS Inc, Chicago, IL). The normality of data distribution was assessed by the Kolmogorov- Smirnov test. All values are expressed as mean +- SD or counts (per- centage) unless otherwise specified. Comparisons were made by using chi-square test or Fisher exact test for categorical data and the Mann-Whitney U test for continuous variables. Correlation of IMA with CT findings was assessed by Spearman’s correlation coefficient. P b .05 was considered statistically significant.

Results

A total of 227 patients were diagnosed as AA between January 2016 and May 2016. Non-complicated appendicitis was found in 174 (76.7%)

Table 1

Clinicopathological characteristics of the patients (n = 62)

Characteristics n (%)

Age (y) 30.1 +- 10.9 y (18-70)

Gender

Male 33 (53.2%)

Female 29 (46.8%)

WBC (uL) 15.1 +- 4.7 (7-33)

IMA (ABSU) 0.647 +- 0.09 (0.477-0.874)

US (n = 51)

Normal 13 (21.0%)

Appendicitis without perforation 39 (62.9%)

Appendicitis with perforation 7 (11.3%) CT (n = 17)

Normal 0

Appendicitis without perforation 12 (70.5%)

Appendicitis with perforation 5 (29.5%) Type of surgery

Open appendectomy	27 (43.5%)
Laparoscopic appendectomy	35 (56.5%)
Duration of hospitalization (d)	1.9 +- 1.5 (1-9)
Pathological diagnosis
Acute appendicitis	33 (53.2%)
Gangrenous/perforated appendicitis	29 (46.8%)

Age was presented as mean +- SD and range; Duration of hospitalization was presented as median and IQR; other variables were presented as number and percentage.

Hospital stay (d) 1.9 +- 1.4 (1-7) 1.9 +- 1.6 (1-9) .902

Age (y)	29.8 +- 10.7 (18-70)	30.4 +- 11.3 (19-60)	.921
Gender Male	20 (60.6%)	13 (44.8%)	.218
Female	13 (39.4%)	16 (55.2%)
WBC (uL)	15.1 +- 3.4 (7-21.6)	15.2 +- 5.9 (7-33)	.703
IMA (ABSU) US	0.618 +- 0.09 (0.477-0.824)	0.682 +- 0.08 (0.529-0.874)	.012 .273
Normal	7 (21.2%)	6 (23.1%)
Appendicitis without perforation Appendicitis with	25 (75.8%) 1 (3%)	14 (53.8%) 6 (23.1%)
perforation CT			.031
Normal	0	0
Appendicitis without perforation	7 (100%)	5 (50%)
Appendicitis with perforation Type of operation	0	5 (50%)	.954
Open	15 (45.4%)	12 (41.4%)
Laparoscopic	18 (54.6%)	17 (58.6%)

patients while 53 (23.3%) patients had complicated appendicitis. Sixty- two patients (mean age, 30.1 years; range, 18-70) who met the study criteria were included in the study. There were 33 (53.2%) males and 29 (46.8%) females. Twenty-seven (43.5%) patients underwent standard open appendectomy while laparoscopic appendectomy was performed in 35 (56.5%) cases. There was only one conversion from laparoscopy to open surgery, due to the generalized peritonitis from appendicial per- foration. The median length of hospital stay was 1.9 (1-9) days, and no mortality was observed during this period. The pathological diagnoses were AA in 33 (53.2%), and gangrenous/perforated appendicitis in 29 pa- tients (46.8%). The clinical, radiological, and pathological characteristics of the whole population are presented in Table 1.

There was no significant difference in age, gender, WBC count, ultra- sound (US) findings, type of operation, and duration of hospital stay between the two groups (P N .05). On the other hand, there were

Figure. Ischemia-modified albumin levels in patients with acute appendicitis and gangrenous/perforated appendicitis (0.618 +- 0.09 ABSU vs. 0.682 +- 0.08 ABSU, P = .012).

94 M.O. Kilic et al. / American Journal of Emergency Medicine 35 (2017) 92-95

significant differences in CT findings (P = .031) and IMA (P = .012) levels between the groups (Table 2) (Figure).

The correlation between IMA level and CT findings was also statisti- cally evaluated. It was found that there was a strong positive correlation between IMA levels and CT findings in the whole study population (Spearman’s rho = +0.688, P = .003).

Discussion

Appendicial perforation is the initial clinical presentation in a signifi- cant number of patients with AA. In our study, the number of patients with complicated appendicitis may be considered higher than those in the literature. However, it should be noted that both patients with perfo- rated appendicitis and those with gangrenous appendicitis were grouped as complicated appendicitis in the study. In addition, the hospi- tal in where the study was conducted is a reference medical center for the complicated cases. It is known that complicated appendicitis is asso- ciated with increased morbidity and mortality. Therefore, identifying the patients with perforated AA is of great importance for the surgical planning, further treatments, and predicting the course of disease. It is also important for the decision of non-operative therapy that may be con- sidered as an option in cases with non-complicated appendicitis.

Currently there is no specific diagnostic test for determination of appendicial perforation. Often the leukocyte count is used for diagnosis and to predict the disease severity of AA, with a sensitivity rate of up to 92% in previous reports [14]. Despite the low specificity, increased leukocyte levels are also used as an indicator of necrosis in various ischemic-based conditions such as acute mesenteric ischemia and strangulated hernia. Although rises in Leucocyte counts are considered to be associated with the severity of AA [15], it is not accepted as a reliable parameter predicting the extent of disease [9,12]. Consistent with other studies, we found no significant difference in leucocyte count was found between the patients with simple AA and those with gangrenous/perforated appendicitis.

Recently, oxidative stress condition and imbalance in oxidative defense system have been shown to be involved in the pathogenesis of various ischemic-based diseases [16-18]. Oxidative stress is generally defined as the accumulation of reactive oxygen radicals in the body due to the inability in antioxidant defense system [19]. It is well known that mucosal ulceration and bacterial invasion into the muscularis propria due to the luminal obstruction are the early events in the pathogenesis of AA. Subsequently, raise in luminal pressure due to the increased secretion causes mucosal ischemia. Ischemic necrosis of mucosa then results in gangrene and perforation. Therefore, oxidative stress condi- tion, in addition to Inflammatory processes, was considered to be in- volved in the pathology and progression of AA [20-23]. However, the presence of ischemia was not sufficiently evaluated in popular scoring systems such as Alvarado and RIPASA scores [24].

As known, IMA has been previously reported as an indicator of oxidative stress conditions [25]. Many ischemic stressors are released from tissues in Hypoxic conditions, and modify N-terminal amino acids of circulating albumin to a different subform called as IMA [26]. In addition, the production of IMA is related to the production of free oxygen radicals, which increases in oxidative stress conditions. In a study by Satomi et al., superoxide dismutase, one of the free oxygen metabolites, was shown to be correlated with degree of inflammation in AA [27]. Although there are several studies on the relationship between various oxidative stress markers and the diagnosis and/or extent of AA in the literature, the potential role of IMA in AA was inves- tigated in a single study [9]. In that work, both serum levels and tissue levels of several markers of oxidative metabolism including IMA were investigated. Preoperative serum level of IMA was found to be lower in healthy group than in patients with AA while no association between serum level of IMA and extent of appendicitis was revealed. Thus, the value of IMA in the preoperative diagnosis of AA was clearly shown by the authors. Differently from that work, we primarily focused on the

potential role of IMA in predicting the extent of AA, especially gangre- nous/perforated subform. Therefore, patients who had normal appendicial tissue at the pathological examination were not included in the study. According to our findings, serum level of IMA was found significantly higher in patients with flegmaneous/perforated appendici- tis compared to those with simple AA. This result is important because it is the first report indicating the high predictive value of IMA in distinguishing AA and flegmaneous/perforated appendicitis. Actually, the diagnostic value of IMA was mostly investigated in ischemic heart diseases and neurological disorders. There is limited number of study regarding the association of IMA and ischemia-based diseases in general surgery practice [9,28,29]. However, it is well known that ischemia is a critical step in the pathogenesis of various urgent diseases including acute mesenteric ischemia, strangulated hernia, acute pancreatitis, and

AA. Future studies might explore the utility of IMA as a potential novel indicator of ischemia in these diseases or explore potential cut off values for IMA indicating a greater risk of perforation.

In this study, abdominal CT, in addition to IMA, was found to be an indicator of gangrenous/perforated appendicitis. Radiological tests, including abdominal US and CT, are widely used in the diagnosis of AA and predicting the Severity of disease. However, both sonographic and tomographic findings indicating complicated appendicitis are not clear. Appendiceal maximal diameter (N10 mm), periappendiceal fat infiltration, periappendicular abscess, appendicoliths, and ascites are usually accepted as tomographic signs of complicated appendicitis [4,12,13]. In the present study, US was used in all patients whereas CT was the radiological method in patients with suspected clinical, laboratorial, and ultraSonographic findings. All CT scans were evaluated by expert radiologists, and the tomographic criteria of gangrenous/ perforated appendicitis were in accordance with the literature. Al- though there are many studies with controversial results on the predic- tive value of CT in the severity of AA [4,12,30,31], our findings showed that CT was a strong and reliable tool to determine complicated appen- dicitis. However, the disadvantages of CT scan are extra costs, increased staying time in the emergency department, and radiation exposure [32].

Limitations

This study has several limitations. First of all, it was conducted in a single center, which may limit the generalizability of the results. A rela- tively small sample size is another limitation of this work, which makes it difficult to interpret subgroup findings, and patients with a normal appendix on final histopathological examination were not included in the study. However, it should be stated here that the present study focused on the predictive value of IMA in distinguishing between non- complicated simple AA and the gangrenous and/or perforated appendi- citis. Finally, we were not able to control some physiologic parameters (exercise, hydration, etc.) that could influence the serum level of IMA.

Conclusions

This study clearly showed that IMA can be used as a biomarker to distinguish gangrenous/perforated appendicitis from non-complicated simple AA. However, these findings are new, and need to be validated by larger studies that might explore potential ranges of IMA indicating a higher risk of perforation.

Conflict of interest

No thing to declare.

Statement of authorship

Dr Kilic, Dr Guldogan, and Dr Tez have been involved in the concept, design, writing, and editing of the manuscript. Dr Balamir was responsi- ble for the biochemical analyses. Dr. Guldogan and Dr Balamir were also

M.O. Kilic et al. / American Journal of Emergency Medicine 35 (2017) 92-95 95

involved in data gathering and analysis. Dr Kilic and Dr Tez provided critical review and final draft of the manuscript.

References

AJEM