Changes in Thiol-Disulfide Homeostasis of the Body to Surgical Trauma in Laparoscopic Cholecystectomy Patients

Abstract

Objective:

We aimed to investigate the short-term effect of laparoscopic surgery on serum thiol-disulfide homeostasis levels as a marker of oxidant stress of surgical trauma in elective laparoscopic cholecystectomy patients.

Materials and Methods:

Venous blood samples were collected, and levels of native thiols, total thiols, and disulfides were determined with a novel automated assay. Total antioxidant capacity (measured as the ferric-reducing ability of plasma) and serum ischemia modified albumin, expressed as absorbance units assayed by the albumin cobalt binding test, were determined.

Results:

The major findings of the present study were that native thiol (283 ± 45 versus 241 ± 61 μmol/L), total thiol (313 ± 49 versus 263 ± 67 μmol/L), and disulfide (14.9 ± 4.6 versus 11.0 ± 6.1 μmol/L) levels were decreased significantly during operation and although they increased, they did not return to preoperation levels 24 hours after laparoscopic surgery compared to the levels at baseline. Disulfide/native thiol and disulfide/total thiol levels did not change during laparoscopic surgery.

Conclusions:

The decrease in plasma level of native and total thiol groups suggests impairment of the antioxidant capacity of plasma; however, the delicate balance between the different redox forms of thiols was maintained during surgery.

Introduction

Laparoscopic surgery is preferred over open surgery because of advantages that include smaller incisions, less pain after operation, more rapid recovery, and faster return to normal functional status.¹

Currently, laparoscopic cholecystectomy is the gold standard procedure for gallbladder removal.² To achieve a sufficient image for laparoscopy, CO₂ insufflation into the abdominal cavity is performed; however, this affects a number of hemostatic systems. Related to this, published studies have shown specific complications associated with laparoscopic operations. Several studies have addressed the possibility of oxidative stress due to laparoscopic operation.^3–7 The increase in intra-abdominal pressure associated with a pneumoperitoneum greater than normal portal pressure (7–10 mmHg) and the formation of splanchnic ischemia leads to free radical production.⁸ Moreover, manipulation of the intestines, injury to the peritoneum, and inflammatory cell stimulation and hemodynamic changes contribute to oxidative stress during laparotomy.^9–11

In contrast, exposure of the peritoneal cavity to room air with higher oxygen concentration and manipulation of the bowel cause increased inflammatory response and oxidative stress generation in open surgery.^12–14

Many oxidative stress markers, including ischemia modified albumin (IMA), nitric oxide, protein carbonyl content, protein sulfhydryl, malondialdehyde, and lipid peroxides, and total antioxidant capacity (TAC) in laparoscopic and open surgery have been studied previously.^{3–6,15–17}

Thiols are organic sulfur derivatives that contain sulfhydryl residues (-SH) at their active site. Thiols react easily with oxygen-containing free radicals to form disulfides.¹⁸ Once formed, the disulfide bonds can be reduced to thiol groups again; thus, the thiol-disulfide balance is maintained. The formation and breakage of disulfide bonds largely depend on the availability of electron donors and acceptors, which determine the redox potential of the environment.¹⁸ Under physiologic conditions, the extracellular space is known to have a relatively more oxidized redox state than the interior of the cell. The extracellular supply of thiols is critical for maintaining the redox state of the extracellular space.¹⁹ Protein -SH groups are important antioxidant defenses in circulation.²⁰ During surgery, the extracellular redox state may be altered and the sulfhydryl group of thiols can undergo oxidation reactions.

An automated assay involving native and total thiol and disulfide quantitation has been described recently as a method for determining dynamic thiol/disulfide homeostasis.²¹ This new assay is easy to perform in routine clinical laboratories, and it offers a sensitive method for monitoring the oxidative stress status of the human body. Impairment of thiol/disulfide homeostasis levels can be expected during laparoscopy due to ischemia–reperfusion injury. However, the literature contains no data describing thiol/disulfide homeostasis in elective laparoscopic cholecystectomy patients or in open surgery patients.

In the present study, we aimed to examine the short-term effect of laparoscopic surgery on serum thiol-disulfide homeostasis levels as a marker of the oxidant stress of surgical trauma in elective laparoscopic cholecystectomy patients in addition to IMA and TAC.

Materials and Methods

All experiments were carried out in accordance with the tenets of the Declaration of Helsinki (2013 Brazil version) of the World Medical Association. We received approval from the Mugla Sitki Kocman University Scientific Research Ethics Committee for this study and all participants signed written informed consent forms before the study began.

From August 2015 to January 2016, a total of 34 healthy patients (ASA I–II) receiving elective laparoscopic cholecystectomy in the Mugla Sitki Kocman University School of Medicine General Surgery Department for symptomatic uncomplicated cholecystolithiasis and 34 patients (14 male, 20 female) receiving open inguinal–femoral hernia repair operations were enrolled in this randomized prospective controlled study.

Those who had serious cardiopulmonary disorders, liver or kidney function deficiency, acute inflammation, infection in the abdominal wall, were obese, had acute cholecystitis, empyema of the gallbladder, diaphragmatic rupture, ileus, portal hypertension, cirrhosis, fever or other systemic diseases, malignant tumors, or administration of hormone drugs or antioxidants within 3 months before surgery were excluded. All operations were performed by two surgeons of our institution, who were experienced in laparoscopic and open surgical techniques.

All patients were administered antibiotics preoperatively (cefoxitin 1 g intravenous [IV]). Anesthetic induction was performed with propofol (2,6-diisopropylphenol) 2–3 mg/kg (IV), fentanyl (1 μg/kg), and rocuronium (0.1 mg/kg). After endotracheal intubation, anesthesia maintenance was provided with sevoflurane (1%–2%), an air/O₂ mixture (30% O₂), and nitrous oxide 2 L/minute. Once in the operating room, patients were monitored with a Datex Ohmeda S/5 Avance (General Electric, Inc., Madison, WI).

Blood was collected thrice: (1) immediately before anesthesia, (2) immediately after the operation (10 minutes after the release of pneumoperitoneum), and (3) 24 hours after the operation.

Fluid management during the operation was standardized; for intraoperative IV fluids, it comprised a balanced electrolyte solution (Isolyte-S, Eczacıbaşı-Baxter, Istanbul, Turkey) 8–10 mL/kg body weight/hour. Laparoscopic cholecystectomy was performed as commonly accepted, while maintaining CO₂ pressure automatically at 14 mm Hg during the operation. Reverse trendelenburg position was applied in the patients who underwent laparoscopic cholecystectomy.

Complete blood count, urea, creatinine, albumin, protein, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamyltranspeptidase were measured preoperatively, as well as 24 hours postoperatively.

The collected samples were centrifuged at 3500 rpm at 4°C. The resulting serum was frozen at −80°C until analysis.

Serum disulfide/thiol homeostasis measurements were determined with the automated spectrophotometric method described by Erel and Neşelioğlu.²¹ Half of the difference between total thiols and native thiols was recorded as the dynamic disulfide amount. After native thiols (SH) and total thiols were determined, disulfide (SS) amounts, disulfide/total thiol percent ratios (SS/SH+SS), disulfide/native thiol percent ratios (SS/SH), and native thiol/total thiol percent ratios (SH/SH+SS) were calculated.²¹

IMA levels were determined according to the method defined by Bar-Or et al.²² Briefly, 200 μL of patient serum was added to 50 μL 0.1% (w/v) cobalt chloride followed by vigorous mixing and 10 minutes of incubation in the dark at 37°C to allow cobalt binding to albumin. Then 50 μL dithiothreitol (DTT) was added as a coloring agent. After 2 minutes of incubation, 1 mL of 0.9% NaCl was added to stop the reaction. Absorbance values at 470 nm were read using a Shimadzu UV-1201 V spectrophotometer (Shimadzu, Kyoto, Japan). The difference of absorbance units (ABSUs) between control and DTT samples was recorded. The results were quantified as ABSU, and values greater than 0.400 ABSU were accepted as indicative of ischemia.²²

Ferric-reducing ability of plasma (FRAP) was measured using the method of Benzie and Strain with modifications of the assay on a 96-well microplate using a Readwell Touch Elisa plate analyzer (Robonik PVT Ltd., Mumbai, India).²³

Statistical analysis

Calculations were performed using computerized software, SPSS version no. 21.0 (SPSS, Inc., Chicago, IL). The Kolmogorov–Smirnov test was utilized to determine the distribution of the data. Continuous variables with a normal distribution were expressed as mean ± standard deviation, and continuous variables without normal distribution were expressed as median (interquartile range). Quantitative demographic values were evaluated by Student's t-test or Mann–Whitney U-test. Statistical significance was established when the P value was <.05.

Results

The mean age was 46.9 ± 15.1 years (range, 23–85 years, 14 males, and 20 females) in the open inguinal–femoral hernia repair operation group and 46.9 ± 15.1 years (range, 20–80 years, 7 males, and 27 females) in the laparoscopic cholecystectomy group. The duration of the surgical procedure was 45 ± 10 minutes in the laparoscopic cholecystectomy group and 35 ± 15 minutes in the hernia group.

There was no significant change in blood hemoglobin, white blood cell, AST, ALT, urea, creatinine, protein, and albumin levels between groups (Table 1).

Table 1.

Characteristics of the Study Population

Parameters	Inguinal–femoral hernia	Laparoscopic cholecystectomy	P
No. of patients	34	34
Age (years)	46.9 ± 15.1	46.9 ± 15.1	.908
Gender (F/M)	20/14	27/7
Hb, g/dL	13.4 ± 1.7	13.1 ± 1.4	.521
WBC, × 10⁶/L	5650 (2135)	5450 (3100)	.990
ALT, U/L	18 (10)	20 (11)	.492
AST, U/L	18 ± 7	19 ± 5	.233
GGT, U/L	16 (10)	22 (24)	.014^a
Urea, mg/dL	25 ± 8	23 ± 7	.319
Creatinine, mg/dL	0.6 ± 0.2	0.6 ± 0.1	.253
Albumin, mg/dL	4.3 ± 0.4	4.3 ± 0.3	.735
Protein, mg/dL	7.2 ± 0.5	7.1 ± 0.3	.764

Data are expressed as mean ± standard deviation when normally distributed; non-normally distributed data are expressed as median (interquartile range). ^aP < 0.05.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; Hb, hemoglobin; WBC, white blood cell.

Native thiol, total thiol, and disulfide levels were decreased significantly during operation and although increased they did not return to preoperation levels 24 hours after laparoscopic surgery. Thiol-disulfide homeostasis parameters did not change significantly in open inguinal–femoral hernia groups.

The concentration of FRAP in patients who underwent laparoscopic surgery was compared to the value before surgical treatment. The values after the operation and 24 hours after surgery were decreased, although not significantly (533 ± 114, 496 ± 112, and 500 ± 132 μmol/L, respectively) (Table 2). This was the same in open surgery patients (535 ± 114, 530 ± 112, and 521 ± 130 μmol/L) (Table 3).

Table 2.

Thiol-Disulfide Homeostasis, Ferric-Reducing Ability of Plasma, and Ischemia Modified Albumin in Laparoscopic Cholecystectomy Groups

	Preoperation	During operation	24 hours after operation
Native thiol levels, mean ± SD, μmol/L	283 ± 45	241 ± 61^a	266 ± 61^a
Total thiol levels, mean ± SD, μmol/L	313 ± 49	263 ± 67^b	291 ± 66^a
Disulfide levels, mean ± SD, μmol/L	14.9 ± 4.6	11.0 ± 6.1^a	12.4 ± 5.8^a
Disulfide/native thiol levels %, mean ± SD	5.3 ± 1.5	4.6 ± 2.5^c	4.7 ± 2.2^c
Disulfide/total thiol levels %, mean ± SD	4.7 ± 1.2	4.1 ± 2.1^c	4.2 ± 1.7^c
Native thiol/total thiol levels %, mean ± SD	90.4 ± 2.5	91.7 ± 4.2^c	91.5 ± 3.5^c
IMA (absorbance units)	0.519 ± 0.186	0.550 ± 0.106^c	0.560 ± 0.191^c
FRAP, μmol/L	533 ± 114	496 ± 112^c	500 ± 132^c

P < .05 compared to preoperation; ^bP < .01 compared to preoperation; ^cP > .05 compared to preoperation.

FRAP, ferric-reducing ability of plasma; IMA, ischemia modified albumin; SD, standard deviation.

Table 3.

Thiol-Disulfide Homeostasis, Ferric-Reducing Ability of Plasma, and Ischemia Modified Albumin in Inguinal–Femoral Hernia Groups

	Preoperation	During operation	24 hours after operation
Native thiol levels, mean ± SD, μmol/L	256 ± 60	240 ± 67^a	261 ± 62^a
Total thiol levels, mean ± SD, μmol/L	282 ± 66	264 ± 73^a	283 ± 65^a
Disulfide levels, mean ± SD, μmol/L	12.7 ± 6.6	12.0 ± 5.1^a	11.4 ± 5.5^a
Disulfide/native thiol levels %, mean ± SD	4.9 ± 2.5	5.0 ± 2.1^a	4.5 ± 2.5^a
Disulfide/total thiol levels %, mean ± SD	4.4 ± 1.9	4.5 ± 1.7^a	4.0 ± 2.0^a
Native thiol/total thiol levels %, mean ± SD	91.1 ± 3.9	90.9 ± 3.4^a	91.8 ± 4.0^a
IMA (absorbance units)	0.540 ± 0.182	0.575 ± 0.167^b	0.576 ± 0.174^a
FRAP, μmol/L	535 ± 114	530 ± 112^a	521 ± 130^a

P > .05 compared to preoperation; ^bP < .01 compared to preoperation.

FRAP, ferric-reducing ability of plasma; IMA, ischemia modified albumin; SD, standard deviation.

The level of IMA (ABS units) before laparoscopy was 0.519 ± 0.186 and increased (although not significantly) after the operation and 24 hours after laparoscopy to 0.550 ± 0.106 and 0.560 ± 0.191, respectively (Table 2).

The levels of IMA (ABS units) at three time intervals were 0.540 ± 0.182 before open surgery and increased after open surgery and 24 hours after the operation (0.575 ± 0.167, 0.566 ± 0.174) in inguinal hernia patients (Table 3).

Discussion

The major findings of the present study were that native thiol, total thiol, and disulfide levels were decreased significantly during operation and although increased did not return to preoperation levels 24 hours after laparoscopic surgery compared to those at baseline. Disulfide/native thiol and disulfide/total thiol levels did not change significantly during laparoscopic surgery.

Thiols have negative standard reduction potentials; thus, they act as fast electron acceptors. When an oxidant interacts with a thiol group, the oxidant is neutralized to a relatively less toxic byproduct of thiol oxidized to a disulfide. Plasma total thiol (-SH+-S-S-), native thiol (-SH), and disulfide (-S-S-) levels are increasingly utilized for routine clinical diagnosis and monitoring of various human diseases and metabolic disorders.^24,25 Previously, Polat et al. reported significantly decreased sulfhydryl levels in both open hernia repair surgery and laparoscopic preperitoneal hernia repair surgery.²⁶

When undergoing an operation, decreased native and total thiol levels mean that these compounds have been consumed due to oxidative stress during surgery. Monitoring thiol/disulfide homeostasis during surgery may be useful as an early screening test to identify individuals and to establish optimal therapeutic management strategies during surgery.

A pneumoperitoneum is generally established during laparoscopic surgery by continuous insufflation of carbon dioxide into the peritoneal cavity to provide adequate visualization and exposure of structures. The induction of the pneumoperitoneum increases intra-abdominal pressure and leads to a reduction in visceral blood flow causing splanchnic ischemia. Ischemia caused by pneumoperitoneum is transient, and after the release of pneumoperitoneum, normal tissue perfusion is restored.^27,28 Therefore, laparoscopy is considered as representative of an ischemia–reperfusion model, which was confirmed in humans during laparoscopic cholecystectomy.²⁹

In acute ischemic conditions, albumin N-terminal metal binding capacity is reduced and a variant protein is formed, known as IMA.³⁰ IMA has been identified as a sensitive marker for determining alterations in blood flow in the splanchnic area and the visceral area during laparoscopic cholecystectomies.³¹ Meanwhile, a number of studies reported an ischemic effect of surgery by measuring serum IMA.^32,33

In our study, although IMA levels increased during and 24 hours after laparoscopic surgery, we did not demonstrate any significant difference in IMA values, which is an indirect measurement of ischemia–reperfusion injury. These results can be explained by the previous study in which propofol was shown to prevent ischemia–reperfusion injury.³⁴ We also used propofol for anesthetic induction.

Similar to our study, Tsuchiya M et al. also measured levels of plasma ferric-reducing ability as an index of total antioxidant potential during sigmoidectomy under four conditions: open sigmoidectomy with sevoflurane anesthesia, laparoscopic sigmoidectomy with sevoflurane anesthesia, open sigmoidectomy with propofol anesthesia, and laparoscopic sigmoidectomy with propofol anesthesia.¹⁴ They found that propofol anesthesia reduced oxidative stress by functioning as an antioxidant.¹⁴

We determined that TAC (measured as FRAP) although decreased during both open and laparoscopic surgery, did not change significantly. The cause of reduced TAC in the course of surgery can be explained by its consumption in the process of removing free radicals.

The involvement of reactive oxygen species early in the development of surgical stress has not been confirmed due to conflicting published studies. Glantzounis et al.⁴ observed that total antioxidant status levels were decreased significantly 24 hours postoperatively compared to preoperative levels in laparoscopic cholecystectomy; however, the decline was more in the open surgery group.⁴ Zulfikaroglu's study showed a similar pattern as our study that the laparoscopic group had a lower TAC 24 hours after the operation compared to open surgery.⁷ No significant postoperative changes in total antioxidant status in the open or laparoscopic groups were observed in another study.³⁵

This study has some important limitations. First of all, we measured thiol/disulfide homeostasis levels over several time points in peripheral blood. However, it has been shown that oxidative damage can occur at the tissue level without any measurable change in the biomarkers of oxidative stress in the peripheral blood. It is not possible to measure oxidative stress in blood that would correlate with tissue oxidative stress.³⁶ While systemic oxidative stress may reflect total tissue injury, local oxidative stress is representative of local tissue trauma.

Conclusion

Footnotes

Disclosure Statement

No competing financial interests exist.

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