Article

Plasma oxidative-stress parameters and prolidase activity in patients with various causes of abdominal pain

a b s t r a c t

Purpose: We aimed to investigate the Predictive power of plasma prolidase activity and oxidative-stress parameters for distinguishing in patients with various causes of non-traumatic abdominal pain who pre- sented to the emergency department.

Methods: This study enrolled 100 consecutive adult patients and 100 age- and sex-matched healthy con- trols. The patients were divided into surgically treated patients (STP); medically treated patients (MTP) and Nonspecific abdominal pain patients. As predictors of early oxidative changes, the plasma prolidase activity, Total oxidant status \(TOS\), total antioxidant status \(TAS\), and oxidative stress index were assessed using a novel automated method.

Results: No significant difference was observed between the patients and the controls with respect to age or sex (p = 0.837 and 0.188, respectively). The plasma TOS, OSI value, and prolidase activity were signif- icantly higher in the patients with abdominal pain than in the controls (p < 0.001, p = 0.001, and p < 0.001, respectively); however, there was no significant difference in the TAS (p = 0.211). The mean plasma TOS, OSI value, and prolidase activity differed significantly among the three groups (p < 0.001, p = 0.001, and p < 0.001, respectively). The STP had the highest TOS and prolidase activity. However, there was no significant difference in the mean plasma TAS in either group of patients (p = 0.419).

Conclusion: The plasma prolidase activity and TOS level, as biomarkers of oxidative stress, enable dis- crimination of patients with NSAP from those with surgical abdominal pain that requires emergent sur- gical treatment.

(C) 2019

Introduction

Background

Acute abdominal pain constitutes 5-10% of all emergency admissions. In general, 20-25% of acute abdominal pain patients are hospitalized and require emergency surgery; in contrast, no underlying reason can be found, and the pain resolves sponta- neously, in 35-40% of patients, who are regarded as having non- specific abdominal pain (NSAP) [1,2].

* Corresponding author at: University of Health Sciences, Department of Emer- gency Medicine, Haseki Research and Training Hospital, Millet Street, Zip Code: 34096, Fatih, Istanbul, Turkey.

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

Patients with acute abdominal pain who present to the emer- gency department (ED) should be evaluated and a differential diag- nosis made immediately. Emergency physicians determine which NSAP patients require emergency surgery and the appropriate follow-up duration. Only 10% of patients with abdominal pain require surgical intervention [3]. Therefore, new laboratory mark- ers are needed to determine which patients with abdominal pain require medical treatment and immediate surgical evaluation. The Biochemical parameters that enable diagnosis/differential diagnosis of patients with acute abdominal pain in the ED are unclear; this is an important clinical issue. Prolidase alone does not provide information on disease activity. Thus, prolidase should be evaluated together with other serum biochemical markers [4]. The oxidant/antioxidant status and prolidase activity might be use- ful for diagnosis of acute appendicitis, a frequent cause of acute abdominal pain [5-8]. Prolidase activity, an indicator of collagen

https://doi.org/10.1016/j.ajem.2019.04.032

0735-6757/(C) 2019

turnover, is altered in several diseases: increased in liver diseases, various cancers, including breast cancer, Renal cell carcinoma, and Lung cancers, bronchial asthma, and acute pancreatitis [9-15]. Additionally, prolidase activity is increased due to collagen deteri- oration in diseases characterized by chronic inflammation [16,17]. However, no study has compared the oxidative-stress parame- ters and prolidase activity in patients with abdominal pain of var- ious causes. Also, the lack of biochemical indicators for diagnosis and differential diagnosis of acute abdominal pain is a major clin- ical issue. Thus, we investigated the predictive power of plasma prolidase activity, Total oxidant status , total antioxidant sta- tus (TAS), and the oxidative stress index (OSI) for differentiation of NSAP, medically treated, and surgically treated abdominal pain in

patients who present to the ED.

Methods

Study design and setting

This study was conducted in accordance with the 1989 Declara- tion of Helsinki and was approved by the Ethics Committee of the Faculty of Medicine, University of XXXX, XX, XXX (No. B.30.2.HR.0. 20.05.00.050.01.04-70). This study was funded by the XXXX University Board of Scientific Research Projects (No. 13048).

From April 2013 to March 2014, this prospective case-control study enrolled 100 consecutive adult patients (56 females and 44 males; age range, 18-65 years) who were admitted due to abdom- inal pain to our tertiary-care university hospital ED. One-hundred age- and sex-matched healthy volunteers were also enrolled. Patients were provided basic life support at presentation and advanced life support if required. After vital functions were moni- tored, written informed consent was obtained directly from the patients after their abdominal pain was controlled using appropri- ate medications. Furthermore, the healthy volunteers were informed about the study protocol, and written consent was obtained from all participants prior to their participation in the study. The differential diagnosis of acute abdominal pain in patient groups was made by anamnesis and physical examination of the abdomen, and radiological examination. A negative or inconclusive ultrasound was followed by computed tomography. Subsequently, the patients were divided into surgically treated patients (STP; group I), medically treated patients (MTP; group II), and patients with NSAP (group III).

Selection of participants

The inclusion criteria were adult patients (>=18 years of age) with a >1-week history of abdominal pain. The exclusion criteria were as follows: >18 years of age, traumatic abdominal pain, con- ditions that may have affected oxidative markers, such as chronic medical disorders (i.e., congestive heart failure, chronic obstructive lung disease, diabetes mellitus, coronary artery disease, peripheral vascular disease, chronic renal failure, stroke, hypertension, active somatic-psychiatric disease, rheumatic arthritis, Multiple sclerosis, Parkinson’s disease, or malignancy); alcohol, tobacco, and/or ecstasy use; and being pregnant or exhibiting elevated human chorionic gonadotropin levels detected by a quantitative hCG blood test (b-hCG). None of the subjects were taking drugs known to affect lipid or lipoprotein metabolism, and care was taken to exclude those taking anabolic drugs, diuretics, vitamins, or other antioxidants (e.g., vasoactive and beta-blocking agents).

Blood sampling

Venous blood samples (5 mL) were drawn from the antecubital vein at the time of admission without the use of medications or serum infusions, and diagnostic Imaging techniques that may affect the levels of plasma TOS and TAS levels, and prolidase activ- ity. Blood samples were collected in heparinized tubes, and imme- diately stored on ice at 4 ?C. Plasma was separated by

centrifugation at 4000 rpm for 5 min, and was stored at –80 ?C

until assessment of prolidase activity, TOS, TAS, and OSI.

Total antioxidant status

The plasma TAS was measured using the fully automated colori- metric assay developed by Erel [18]. based on measurement of the level of OH radicals. This assay determines the antioxidative capac- ity of a sample against the potent reactions triggered by the OH radical. In this method, 2,2′-azinobis-3-ethyl benzothiazoline-6- sulfonic acid radical (ABTS radical) loses its blue or green color according to the antioxidant concentration and capacity. The results were read by spectrophotometry at 660 nm using an auto- mated analyzer (RF-1501(R), Shimadzu Co.(R), Kyoto, Japan). This assay is based on oxidization of ABTS to ABTS+ by hydrogen perox- ide. The results are expressed as millimoles Trolox equivalent per liter (mmol Trolox equiv/L). The precision of the assay is >3%.

2.5. Total oxidant status

The plasma TOS was analyzed using a novel automated mea- surement method developed by Erel [19]. Oxidants in the sample oxidize the ferrous ion-o-dianisidine compounds to ferric ion; glyc- erol accelerates this reaction threefold. Ferric ions form a colored complex with xylenol under acidic conditions, and the intensity of the color is directly proportional to the oxidant level. We used H2O2 to calibrate the assay. The results are expressed as micro- moles H2O2 equivalent per liter (lmol H2O2 equiv/L). This assay has a precision of >2%.

Oxidative stress index

OSI is an indicator of the degree of oxidative stress. The OSI was calculated according to the following formula: OSI (arbitrary units) = (TOS, lmol H2O2 equiv/L) / (TAS, lmol Trolox equiv/L) x 10 — 1.

Prolidase measurement

Plasma prolidase activity was determined using the Gultepe [20]. optimized method, which is a modification of Myara and Chi- nard’s methods [21,22]. The plasma prolidase activity was mea- sured by a photometric method based on the principle of establishing a colorful compound with ninhydrin under the effect of heat in an acidic environment with proline created by mediation of the prolidase enzyme while using glycyl and proline as sub- strates. The intensity of the color is dependent on the concentra- tion of proline. The free proline concentration was measured by a spectrophotometric method (RF-1501(R)). Activity was described

as the quantity of prolidase required to convert 1 lmol substrate

in 1 min. The results are expressed at units per liter (U/L).

Statistical analyses

The required sample size was calculated by power analysis before data collection. It was estimated that at least 88 participants and 88 controls would be required to detect significant differences

among the types of abdominal pain with a power of 95% and an alpha error of 5%.

All analyses were conducted using SPSS statistical software (version 11.5 for Windows; SPSS, Chicago, IL). Numerical data (e.g., oxidative/antioxidative status parameters; TOS; TAS; OSI value; and prolidase activity) are expressed as means +- standard deviations (SD), and categorical variables (gender and age) as num- bers (n). Intergroup comparisons (controls vs. patients) were con- ducted by chi-squared test for normally distributed data and Mann-Whitney U test for non-normally distributed data. One- way analysis of variance (ANOVA) was used to assess normally dis- tributed (by Kolmogorov-Smirnov Z-test) numerical values according to the cause of abdominal pain (intragroup compar- isons). The predictors including plasma levels of TOS, TAS and pro- lidase activity and OSI values, age and gender that can be significant on the STP and NSAP groups were modeled by univari- ate and multivariate logistic regression analysis. Confidence inter- vals were given at the 95% level and a value of p < 0.05 was considered to indicate significance.

Results

The mean age of the 100 patients was 39.31 +- 17.66 years (range, 18-65 years) and 56 (56%) were females. The mean age of the 100 healthy volunteers was 37.67 +- 13.77 years (range, 18- 63 years) and 53 (53%) were females. The causes of abdominal pain are listed in Table 1.

There was no significant difference between the patients and the controls in terms of age (p = 0.837) or sex (p = 0.188). The mean plasma TAS was slightly higher in the patients with abdominal pain than in the controls (1.09 +- 0.21 and 1.05 +- 0.23, respectively; p = 0.211). The mean plasma OSI value was significantly higher in the patients than in the controls (p = 0.001). Similarly, the plasma prolidase activity and TOS were significantly higher in the patients than in the controls (both p < 0.001).

The demographic characteristics, plasma prolidase activity, TOS, OSI value, and TAS are shown in Table 2. Among the patients, 33 were surgically treated, 34 were medically treated, and 33 had NSAP. There were significant differences among the three groups in the mean plasma TOS and prolidase activity (p > 0.001; Table 3 and Figs. 1 and 2). The mean plasma prolidase activity was higher

Table 1

Distribution of 100 adult patients according to the cause of abdominal pain; STP, MTP, and NSAP.

Cause of abdominal pain

STP group I (n = 33)

n (%)

MTP group II (n = 34)

n (%)

NSAP group III (n = 33)

Acute appendicitis

6 (18)

acute cholecystitis

6 (18)

Ileus

5 (15)

Tuba ovarian abscess

2 (6)

Ovarian torsion

3 (9)

gastrointestinal perforation

6 (18)

Hydatid cyst rupture

1 (3)

Acute mesenteric ischemia

4 (13)

Acute gastritis

6 (17)

Hepatosteatosis

2 (6)

Peptic ulcus

4 (12)

Urinary tract infection

4 (12)

Urolithiasis

4 (12)

acute gastroenteritis

6 (17)

Acute diverticulitis

2 (6)

Pelvic inflammatory disease

2 (6)

UlcerativE colitis

4 (12)

Note: Data are percentages (%) or n.

Abbreviations: STP, surgically treated patients; MTP, medically treated patients; NSAP; nonspecific abdominal pain.

Table 2

Demographic data and plasma parameters of 100 adult patients with abdominal pain and 100 healthy controls.

Characteristic Control group Patients with p

n = 100

abdominal pain

n = 100

Age (years) 37.67 +- 13.77

39.31 +- 17.66

0.837

Gender (female/male) 53/47

56/44

0.188

TAS (mmol Trolox(R) equiv/L) 1.05 +- 0.23

1.09 +- 0.21

0.211

TOS (lmol H2O2 equiv/L) 25.73 +- 7.59

34.37 +- 10.76

<0.001

OSI (arbitrary units) 2.54 +- 0.90

3.40 +- 2.43

0.001

Prolidase (IU/L) 839.00 +- 148.07

1002.16 +- 268.15

<0.001

Note: Data are means +- SD or n.

Intergroup comparisons (controls vs. patients) were performed by chi-squared and Mann-Whitney U tests, as appropriate.

Abbreviations: STP, surgically treated patients; MTP, medically treated patients; NSAP; nonspecific abdominal pain; OSI, oxidative stress index; TAS, total antioxi- dant status; Trolox(R), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; TOS, total oxidant status.

in group II than in group III (999.80 +- 247.69 and 871.58 +- 128.74, respectively; Fig. 2) and was highest in group I (1206.27 +- 242.63; Fig. 2). The plasma OSI value was significantly increased (p = 0.001), whereas there was no significant difference in the TAS, among the three patient groups (p = 0.419) (Table 3).

The univariate and multivariate logistic regression analysis demonstrated that plasma TOS and prolidase levels remained inde- pendent predictors of surgery in STP group. According to multivari- ate logistic regression analysis, TOS is the most important predictor for diagnosis of STP, with an odds ratio of 1.163 [95% confidence interval (CI): 1.081-1.250, p = 0.001; Table 4].

The results of logistic regression analysis further demonstrated that plasma TOS and prolidase levels were independently associ- ated with NSAP in patients group. According to multivariate logis- tic regression analysis, the most important predictor for diagnosis of NSAP patients was TOS with an odds ratio of 1.541 [95% confi- dence interval (CI): 1.251-1.901, p = 0.001; Table 5].

Discussion

This is the first in vivo study of prolidase activity, TOS, TAS, and OSI value in adult patients with abdominal pain of various causes who presented to the ED. In addition, the novel automated mea- surement method of Erel [18,19], was used to assess the plasma TOS and TAS. The key findings were that plasma prolidase activity, TOS, and OSI value were significantly higher in the patients than in the controls.

Oxidative stress is defined as an imbalance between the pro- duction of reactive oxidants and their elimination by antioxidants, and can be caused by acute inflammation, Ischemia-reperfusion injury, and surgical trauma [5,7,23]. Patients with acute appendici- tis have increased oxidative stress and impaired antioxidant defenses [5,6]. The role of oxidative stress-induced acute inflam- matory responses in pediatric and adult patients with abdominal pain arising from acute appendicitis has been reported [6,7,24,25]. For example, Yilmaz et al. [6] reported that patients with acute appendicitis had significantly higher plasma levels of thiobarbitUric acid reactive substances (TBARS), an indicator of free radical-induced oxidative stress, and significantly lower levels of plasma thiol groups (SH; an indicator of antioxidant capacity) com- pared to the controls. In a case-control study, Ozdogan et al. [5] showed that the plasma TAS is inversely correlated with the sever- ity of acute appendicitis.

Consistent with these findings, we found that the TOS and the OSI value were significantly elevated in patients with abdominal pain of various causes compared to healthy controls. By contrast,

Table 3

Plasma parameters in 100 adult patients according to the cause of abdominal pain; STP, MTP and NSAP.

Characteristic

STP group I n = 33

MTP group II n = 34

NSAP group III n = 33

p

TAS (mmol Trolox(R) equiv/L)

1.09 +- 0.20

1.07 +- 0.25

1.13 +- 0.15

0.419

TOS (lmol H2O2 equiv/L)

41.05 +- 9.74

34.80 +- 10.49

26.94 +- 6.56

<0.001

OSI (arbitrary units)

3.89 +- 3.99

3.84 +- 1.07

2.41 +- 0.64

0.001

Prolidase (IU/L)

1206.27 +- 242.63

999.80 +- 247.69

871.58 +- 128.74

<0.001

Note: Data are means +- SD or n.

Intragroup comparisons (MIDAS groups) were performed by one-way analysis of variance (ANOVA).

Abbreviations: STP, surgically treated patients; MTP, medically treated patients; NSAP, nonspecific abdominal pain; OSI, oxidative stress index; TAS, total antioxidant status; Trolox(R), 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; TOS, total oxidant status.

patients with abdominal pain had a non-significantly higher TAS than the controls. Taken together, these findings suggest that an impaired antioxidant response may reflect a severely disturbed oxidant/antioxidant balance in patients with abdominal pain, lead- ing to increased oxidative stress.

Koltuksuz et al. [25] assessed the levels of Malondialdehyde \(MDA\), as an oxidative activity, and of superoxide dismutase \(SOD\), as a marker of the antioxidant reserve, in the plasma of patients with acute appendicitis. The patients had an elevated SOD level compared to the controls as well as an increment of MDA. Indeed, we found that the mean TOS and the mean OSI value were significantly higher in patients with abdominal pain than in the controls; however, the mean TAS was similar. This indicates enhanced oxidative damage and an impaired antioxidant defense in patients with abdominal pain.

Collagen, a component of connective tissue, plays a critical role in inflammation and wound healing [17]. Prolidase is impor- tant for collagen turnover, inflammation, tissue fibrosis, and skeletal abnormalities. Prolidase activity alone without other bio- chemical markers may not provide useful information on disease activity [4].

Changes in prolidase activity and oxidative-stress parameters are associated with the development of several diseases [26-28]. For example, Duygu et al. [27] reported that the plasma prolidase activity and oxidative-stress parameters were high, and the antiox- idant level low, in patients with chronic Hepatitis C virus infection. Hilali et al. [28] showed that serum prolidase activity, TOS, and OSI value were significantly higher in patients with polycystic ovary syndrome than in controls.

In this study, the mean plasma prolidase activity, TOS, and OSI value were significantly elevated in the patients with abdominal pain compared to the controls. The increased prolidase activity might be attributable to increased oxidative stress and an impaired antioxidant defense in patients with abdominal pain of various causes.

The peak plasma prolidase activity, TOS, and OSI value increased in proportion to the cause of abdominal pain, such that the STP group exhibited the highest values of these parameters. On the basis of univariate and multivariate analysis, plasma TOS and prolidase levels were found to be an independent predictors for diagnosis of STP group. Likewise, this analysis showed that the independent predictors of NSAP group were TOS and prolidase. In the present study, an increase in prolidase activity and TOS levels indicated not only the presence of disease but also separa-

tion of abdominal pain.

The high prolidase activity in the STP group suggests that mea- surement of prolidase activity may help determining the tissue col- lagen destruction and the emergent status of the patient. It may also allow early determination of the need for surgery and so decrease the mortality and morbidity rates. The high prolidase activity and TOS showed that tissue damage can influence collagen turnover. The accelerated collagen metabolism in the STP and MTP compared to the NSAP groups suggests that failure in the structure of collagen related structural disorder occur due to metabolic events.

The present study has several limitations. First, we did not quantify the severity of abdominal pain using a Visual analogue scale (VAS). Therefore, the TOS, TAS, and prolidase activity could

Fig. 1. Plasma TOS according to the cause of abdominal pain; STP, MTP, and NSAP.

Fig. 2. Plasma prolidase activity according to the cause of abdominal pain; STP, MTP, and NSAP.

Table 4

Independent predictors of surgery in STP group identified in univariate and multivariate logistic regression analysis.

Multivariate adjusted model Univariate unadjusted model

B

P

OR

95% Cl

B

P

OR

95% Cl

TOS

0.151

0.001

1.163

1.081

1.250

0.098

0.001

1.103

1.051

1.157

Prolidase

0.007

0.001

1.007

1.004

1.011

0.005

0.001

1.006

1.003

1.008

Age

0.003

0.858

1.003

0.968

1.040

Gender

0.125

0.848

1.133

0.317

4.047

TAS

–1.941

0.189

0.144

0.008

2.605

Abbreviations: B, standardized regression coefficient; OR, odds ratio; CI, confidence interval; P, statistical significance; STP, surgically treated patients.

Table 5

Independent predictors for diagnosis of NSAP group identified in univariate and multivariate logistic regression analysis.

Multivariate adjusted model Univariate unadjusted model

B

P

OR

95% Cl

B

P

OR

95% Cl

TOS

–0.433

0.001

1.541

1.251

1.901

–0.143

0.001

1.153

1.081

1.231

Prolidase

–0.012

0.001

1.012

1.005

1.018

–0.004

0.001

1.004

1.002

1.006

Gender

1.988

0.039

7.303

1.103

48.344

Age

0.013

0.672

1.013

0.954

1.075

TAS

0.004

0.002

1.012

1.006

1.018

Abbreviations: B, standardized regression coefficient; OR, odds ratio; CI, confidence interval; P, statistical significance; NSAP, nonspecific abdominal pain.

not be compared according to Pain severity. Also, prolidase activ- ity, TOS, TAS, and OSI value, which may affect long-term outcomes, were not assessed in the patients with STP and MTP following hos- pitalization. These issues should be considered in future studies involving patients with abdominal pain of various causes.

In conclusion, the plasma TOS level and prolidase activity had diagnostic value in patients with abdominal pain of various causes. Thus, an increased plasma prolidase activity, and TOS level indicate an unfavorable oxidant/antioxidant balance in patients with abdominal pain. The results of logistic regression analysis revealed that TOS and prolidase activity were independently associated with STP and NSAP groups. For rapid and accurate clinical decision-making, the plasma prolidase activity and TOS level might enable discrimination between patients with NSAP and those with surgical abdominal pain that requires emergency surgical treat- ment. These tests may also reduce costs and the duration of stay in the ED. Further Controlled clinical trials involving larger num- bers of subjects are warranted.

Conflict of interests

None.

Funding and support

This study was funded by the Harran University Board of Scien- tific Research Projects (No. 13048), Sanliurfa, Turkey. This study was conducted in accordance with the 1989 Declaration of Helsinki and was approved by the Ethics Committee of the Faculty of Med- icine, University of Harran, Sanliurfa, Turkey.

Author contributions

L.A and O.S designed this study. L.A, M.T.G and H.K supervised the overall data collection process, had full access to all the data in the study, and takes responsibility for the integrity of the data.

L.A and S.C conducted the data analysis. O.S and S.C wrote the ini- tial draft of the article. All authors provided substantial review and feedback on the final version of the article. O.S takes responsibility for the paper as a whole.

All authors have read and approved the submitted manuscript. This manuscript has not been submitted nor published elsewhere in whole or in part.

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