The Impact of the Pre-operative Neutrophil-lymphocyte Ratio as the Predictive Marker of Post-operative Weight Loss and Improving Diabetes in Sleeve Gastrectomy.

doi:10.21203/rs.3.rs-131065/v1

Download PDF

Research article

The Impact of the Pre-operative Neutrophil-lymphocyte Ratio as the Predictive Marker of Post-operative Weight Loss and Improving Diabetes in Sleeve Gastrectomy.

https://doi.org/10.21203/rs.3.rs-131065/v1

This work is licensed under a CC BY 4.0 License

You are reading this latest preprint version

Background: The aim of this study was to investigate the impact of the neutrophil-lymphocyte ratio (NLR) in sleeve gastrectomy (SG).

Methods: 15 obese patients were enrolled in this study. They consisted of 5 males and 10 females: mean body weight (BW) 127.5kg; mean body mass index (BMI) 46.7kg/m2. 10 of these were diabetics who underwent a SG. The impact of the pre-operative NLR on the percentage of excess weight loss (%EWL) and remission of diabetes 1 year post-operative were examined.

Results: The BMI, %EWL and %TWL at 1 year post-operative were 35.1 kg/m2, 46.3% and 26.2%, respectively. Improvements were also evident in the diabetes at 1 year post-operative: complete remission (CR) (No medication and hemoglobin A1c (HbA1c) HbA1c<6.0%) 40%, PR (HbA1c<6.5) 20%; and (decrease of anti diabetic drug and HbA1c<7.0%) 40%. Comparing pre-operative NLR in %EWL<50% and >50% in one (1) year post-operative, <50% was 2.64 and >50% was 2.03 (p<0.05). The NLR in CR and partial remission (PR) was significantly lower than that in improved (Improve) (2.22 vs 3.27, p<0.05).

Conclusions: The pre-operative NLR may be a predictive marker of weight loss and improving diabetes after SG.

Gastroenterology & Hepatology

neutrophil-lymphocyte ratio (NLR)

laparoscopic sleeve gastrectomy (LSG)

percent excess weight loss (%EWL)

diabetes

Metabolic syndrome (MS) is characterized by obesity, diabetes, hypertension (HT) and hyperlipidemia (HL). The incidence of MS has increased along with rapid economic development and an associated change in diet [1]. Consequently, increased attention has been paid to the prevention of MS.

There is strong evidence that bariatric surgery is an effective treatment to keep the long-term weight loss [2–4]. Several reports have shown that bariatric surgery is superior to internal medicine in the treatment of MS [5]. Especially, bariatric surgery has been reported to accomplish complete remission in obese patients with Type 2 diabetes mellitus (T2DM) [6].

The authors have previously reported that duodenal-jejunal bypass (DJB) improved T2DM and liver steatosis by enhanced glucagon like peptide-1 (GLP-1) secretion through increase of bile acids and the proliferation of L cells in the ileum [7].

The laparoscopic sleeve gastrectomy (LSG) was initially used at a stage prior to duodenal switch or gastric bypass in the patients with high surgical risk. Recently, this procedure has a popularity due to the good short-term outcomes and its relatively lower technical difficulties [8, 9]. In Japan, the number of the obese patients who have undergone LSG has been increasing [10].

Obesity and MS were reported to show the disruption of lymphoid tissue integrity, alterations in leukocyte development, and the co-ordination of innate and adaptive immune responses [11]. So, the state of obesity showed impaired immunity.

The neutrophil-to-lymphocyte ratio (NLR) is an available inflammatory marker to predict complications following a variety of major surgical procedures [12–14]. Regarding the correlation between the NLR and bariatric surgery, Da Silva M, et al. reported that the post-operative one (POD1) NLR was associated with thirty (30) day outcomes in LSG [15]. However, the relationships between the NLR and long-term outcomes remains unclear.

The aim of this study was to investigate the impact of the NLR regarding post-operative weight loss and improving diabetes in sleeve gastrectomy (SG).

Patient selection and data collection

Patients were included in this study based on the following indicators: a LSG at the Tokushima University Hospital; aged between eighteen (18) years and sixty (60) years; a body mass index (BMI) of > 35 kg/m2; internal therapy of > 6 months; and co-morbidity with T2DM, HT, HL or sleep apnea syndrome (SAS).

The exclusion criteria were: known malignancies; pregnancy; and conditions associated with poor compliance (psychiatric illness).

The protocol for this research project was approved by a suitably constituted Ethics Committee of the Tokushima University Hospital (ToCMS:3215).

From 2013 to 2018, fifteen (15) patients (five (5) males and ten (10) females; age range from thirty-three (33) years to fifty-six (56) years (mean age 42.7 years); and a mean BMI of 46.7) were referred to the Tokushima University Hospital for treatment of morbid obesity. There were thirteen (13) patients who underwent a LSG. There was no cases with conversion to open SG in these 13 patients. Co-morbidity included the following: ten (10) patients with T2DM; eleven (11) patients with HT; six (6) patients with HL; and eleven (11) patients with SAS. A mean hemoglobin A1c (HbA1c) was 6.6 (4.9–8.5).

Data were collected retrospectively from medical records and supplemented with data and laboratory results.

Technical description of an LSG

“The surgical techniques for the LSG procedures have been previously published [31].” In brief, using 5-port laparoscopic technique, LSG was performed. The greater curvature and the angle of His were dissected to staple the gastric fundus and greater curvature parallel to a gastric fiber, which was inserted in the stomach through the esophagus. The bougie was not used in our procedure. Stapling (total five (5) to eight (8) times) was started from a distance of 5 cm to 8 cm from the pylorus on the greater curvature side toward the angle of His. This resulted in a tube-like stomach with a volume of approximately 100 mls made from the lesser curvature only. The staple line was reinforced by 3 − 0 PDS and vicryl continuous sutures. In case of suspected severe adhesion preoperatively, open SG was selected in our department. In this series, two (2) cases underwent open SG, because of previous upper abdominal operations.

NLR, prognostic nutritional index (PNI) and ABCD score

The NLR and PNI were calculated pre-operative and three (3) months post-operative. The NLR was calculated as the absolute neutrophil count divided by the absolute lymphocyte count. The PNI was calculated as described previously [16]; briefly, PNI=[10 × albumin (g/dl)]+[0.005 × total lymphocyte count (µl)]. The ABCD score was composed of the patient's age (A), body mass index (B), C-peptide level (C), and duration of T2DM (years) (D) [17]. In this study, the remission of T2DM after SG was evaluated using the ABCD score.

Evaluation of T2DM resolution

The resolution of T2DM was evaluated using the patient data at twelve (12) months after surgery. Complete remission (CR) was defined as no medication required and HbA1c < 6.0%, partial remission (PR) as no medication required and HbA1c < 6.5%, improved (Improve) as medication reduced and HbA1c < 7.0% and no change (NC) as HbA1c ≥ 7.0%, regardless of medication [18].

Post-operative management

After the SGs, the patients were started with water on day (1) post-operative and a liquid diet on days four (4) or five (5) post-operative. A thrombosis prophylaxis was administered twice a day for a week.

After discharge, the patients were followed up once at one (1) or two (2) months. At outpatient’s clinic, the body weight (BW), blood test and the state of obesity-related disease in the patients were evaluated. The percent excess weight loss (%EWL) and percent total weight loss (%TWL) were checked at one (1) year post-operative. Excess weight was defined as the subject's baseline weight minus the ideal weight that would equate to a BMI of 22.

Statistical analysis

The t-test was used for statistical analysis of the continuous variables. For all tests, p < 0.05 was interpreted as significant. The values for each continuous variable were expressed as a mean ± the standard deviation (SD).

An overview of the long-term outcomes after the LSGs is given in Table 1. The BMI, %EWL and %TWL in one (1) year post-operative was 35.1 kg/m2 (30.6–44.4), 46.3% (35.5–62.6), and 26.2% (14.3–38.9), respectively. Regarding the resolution of T2DM, there were 40% of patients in CR, 20% in PR, and 40% in Improve. HbA1c at one (1) year post-operative was significantly lower than that at pre-operation (6.6 vs 5.7, p < 0.05). Other obesity related diseases: HT 64%; HL 67%; and SAS; 91% had also improved at one (1) year post-operative. The NLR at three (3) months post-operative was significantly lower than that at pre-operation (2.53 vs 1.84, p < 0.05) (Fig. 1a). Comparing the pre-operative NLR in %EWL < 50% and ≥ 50% at one (1) year post-operative, < 50% was 2.64 and ≥ 50% was 2.03 (p < 0.05) (Fig. 1b). In addition, the preoperative NLR in 30%≤%TWL was lower than that in 30%>%TWL at postoperative one (1) year (2.89 vs 2.15, p = 0.09) (Fig. 1c). However, other pre-operative factors did not correlate with the %EWL at one (1) year post-operative (Table 2). Regarding the resolution of T2DM, the NLR in CR and PR was significantly lower than that in Improve (2.22 vs 3.27, p < 0.05) (Fig. 1d). Other pre-operative factors including the ABCD score did not correlate with the resolution of T2DM at one (1) year post-operative (Table 3). In our bypassed case, a diabetic obese patient with preoperative NLR 3.84 and ABCD score 6 (Preoperative BMI: 38.4 kg/m2, HbA1c: 11.0%) showed 75.5% in %EWL and CR in DM remission in postoperative 1 year after laparoscopic sleeve gastrectomy with bypass. So, preoperative NLR was effective in the selection of operative procedure (SG or bypass).

Table 1

Long-term outcome after SG.
Factors	n = 15
BMI in postoperative 1 year	35.1 kg/m2 (30.6–44.4)
%EWL in postoperative 1 year	46.3% (35.5–62.6)
%TWL in postoperative 1 year	26.2% (14.3–38.9)
Improvement of obesity-related disease	T2DM; CR 40%/ PR 20%/ Improve 40%
in postoperative 1 year	Hypertension 64%
	Hyperlipidemia 67%
	Sleep apnea syndrome 91%
HbA1c (%) in postoperative 1 year	5.7 (4.8–7.0)

Table 2

The relationships between preoperative factors and %EWL
Preoperative factors	%EWL in postoperative 1 year		p value
Preoperative factors	< 50%	50%≤	p value
Age (y.o.)	42.5 ± 7.5	42.4 ± 7.8	0.98
Gender (male/ female)	3/ 5	2/ 3	0.93
BW (kg)	124.4 ± 26.3	135.8 ± 21.3	0.47
BMI (kg/m²)	46.1 ± 8.3	49.6 ± 7.1	0.49
Diabetes (+/ -)	5/ 3	3/ 2	0.93
ABCD score	4.20 ± 0.75	5.33 ± 1.25	0.37
NLR	2.64 ± 0.60	2.03 ± 0.17	< 0.05
PNI	49.7 ± 4.7	45.1 ± 6.5	0.25

Table 3

The relationships between preoperative factors and resolution of T2DM
Preoperative factors	Resolution of T2DM in postoperative 1 year		p value
Preoperative factors	CR/ PR	Improve	p value
Age (y.o.)	41.5 ± 4.9	43.8 ± 5.4	0.56
BW (kg)	130.8 ± 22.0	109.0 ± 19.5	0.19
BMI (kg/m²)	45.5 ± 8.1	40.1 ± 3.5	0.30
HbA1c (%)	7.4 ± 0.8	7.5 ± 0.8	0.96
C peptide (ng/ml)	2.93 ± 1.41	4.02 ± 1.11	0.39
ABCD score	4.67 ± 1.89	4.5 ± 0.5	0.88
NLR	2.22 ± 0.36	3.27 ± 0.74	< 0.05
PNI	51.8 ± 1.92	48.0 ± 7.80	0.34

This study was designed to investigate the impact of the pre-operative NLR as the predictive marker of post-operative weight loss and improving diabetes in SG.

A SG, in which 80% of the stomach is removed along the greater curvature but the intestinal anatomy is unchanged, has been gaining in popularity. A SG is considered as a definitive procedure for the treatment of morbid obesity and obesity-related diseases. The number of SGs has been increasing in many countries [19–21]. A SG is successfully performed by laparoscopy in 99.7% of cases, with relative safety [22].

The resolution rates of obesity-related diseases in LSG were reported for: diabetes (58.6%); HT (38.8%); HL (63%); and SAS (91.2%) [23]. Regarding the postoperative weight loss, %EWL in postoperative 1 year showed less than 50%. As one of the reasons, preoperative BMI was relatively high (average BMI; 46.7) and the ratio of super-obese patients (BMI > 50 kg/m2) was 40% (6 / 15).

A previous report discussed the mechanism of improving T2DM in bariatric surgery, duodenal-jejunal bypass (DJB) enhanced GLP-1 secretion through increased bile acids and the proliferation of L cells [7]. The authors also reported that DJB changed the composition of gut microbiota and these changes might contribute to some of the benefits of DJB [24]. Ryan KK, et al. reported that bile acids and the bile acid receptor, known as the farnesoid X receptor (FXR) were important molecular targets for the beneficial effects of bariatric surgery [25].

The ABCD score has been well-known as a predictor of the success of T2DM treatment after LSG. In this report, the authors would only recommend LSG for the T2DM patients with an ABCD > 4 [17]. Regarding the predictor of post-operative weight loss after LSG, Seki, et al. reported that the %EWL in the super morbid obesity group (50 ≤ BMI) was significantly lower than that in the mild obesity group (BMI < 35) and reference group (35 ≤ BMI < 50) [26]. However, the ABCD score and pre-operative BMI have no relationship with the resolution of T2DM and post-operative weight loss in the authors’ study. In that study, a low pre-operative NLR correlated with the improvement of T2DM and %EWL ≥ 50 in one (1) year post-operative in SG. Therefore, the pre-operative NLR may be the only predictive marker of post-operative weight loss and improving T2DM in SG.

A high fat diet elevated the intestinal inflammatory cytokine, alongside compromised mucosal barrier integrity with a loss in the tight junction protein (claudin-1) and increased the severity of colitis, which leads to insulin resistance due to inflammation of the liver and adipose tissue [27]. The authors reported that DJB surgery maintained gut permeability through the suppression of gut inflammation. Therefore, DJB might improve insulin resistance by the suppression of inflammation in insulin-target tissue such as the liver and adipose tissue [28]. The role of the NLR was reported to be a marker of intestinal inflammation because it reflected changes in the gut microbiota [29]. Nlrp3 inflammasome sensed the obesity–associated danger-signals and contributed to the obesity–induced inflammation and insulin–resistance [30]. So, the state of pre-operative inflammation may correlate with post-operative weight loss and glucose tolerance. Therefore, the pre-operative NLR may reflect pre-operative intestinal and systemic inflammation and contribute to post-operative weight loss and the resolution of T2DM in SG.

Our study had the limitation that this was not a long-term result especially for weight loss and reversal of co-morbidities. The results were relatively short term for follow up. Further studies are necessary to confirm whether this is a long-term relationship.

The pre-operative NLR may be a predictive marker of weight loss and improving diabetes after SG.

neutrophil-lymphocyte ratio (NLR); laparoscopic sleeve gastrectomy (LSG); sleeve gastrectomy (SG); body weight (BW); Body Mass Index (BMI); type2 diabetes mellitus (T2DM); hypertension (HT); hyperlipidemia (HL); sleep apnea syndrome (SAS); percent excess weight loss (%EWL); percent total weight loss (%TWL); glucagon-like peptide 1 (GLP-1); metabolic syndrome (MS); hemoglobin A1c (HbA1c); farnesoid X receptor (FXR); duodenal-jejunal bypass (DJB); standard deviation (SD); post-operative one (POD1); prognostic nutritional index (PNI); complete remission (CR); partial remission (PR); improved (Improve); no change (NC); tight junction protein (claudin-1).

The protocol for this research project was approved by a suitably constituted Ethics Committee of the Tokushima University Hospital (ToCMS:1277-4). Written informed consent was obtained from the patients for the publication. All data generated or analyzed during this study are included in this published article. Hideya Kashihara and the co-authors have no conflict of interest regarding this report. The authors of this study are grateful to the staff at the Department of Surgery, Tokushima University, for important contributions.

Elrazek AE, Elbanna AE, Bilasy SE. Medical management of patients after bariatric surgery: principles and guidelines. World J Gastrointest Surg 2014;6:220–8.
Carlsson LM, Peltonen M, Ahlin S, Anveden Å, Bouchard C, Carlsson B, et al.. Bariatric surgery and prevention of type 2 diabetes in Swedish obese subjects. N Engl J Med. 2012;367:695–704.
Sjöström L, Lindroos AK, Peltonen M, Torgerson J, Bouchard C, Carlsson B, et al; Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med. 2004;351:2683–2693.
Sjöström L, Narbro K, Sjöström CD, Karason K, Larsson B, Wedel H, et al; Swedish Obese Subjects Study. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med. 2007;357:741–752.
Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Nanni G, et al. Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomized controlled trial. Lancet 2015;386:964–73.
Buchwald H, Estok R, Fahrbach K, Banel D, Jensen MD, Pories WJ, et al. Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med 2009;122: 248–256.e245.
Kashihara H, Shimada M, Kurita N, Sato H, Yoshikawa K, Higashijima J, et al. Duodenal-jejunal bypass improves diabetes and liver steatosis via enhanced glucagon-like peptide-1 elicited by bile acids. J Gastroenterol Hepatol. 2015 Feb; 30(2): pp308-15.
Felberbauer FX, Langer F, Shakeri-Manesch S, Schmaldienst E, Kees M, Kriwanek S, et al. Laparoscopic sleeve gastrectomy as an isolated bariatric procedure: intermediate-term results from a large series in three Austrian centers. Obesity Surgery. 2008;18(7):814–818.
Topart P, Becouarn G, Ritz P. Comparative early outcomes of three laparoscopic bariatric procedures: sleeve gastrectomy, Roux-en-Y gastric bypass, and biliopancreatic diversion with duodenal switch. Surgery for Obesity and Related Diseases. 2012;8(3):250–254.
Japan Society for Endoscopic Surgery 13^th Nationwide Survey of Endoscopic Surgery in Japan. Journal of Japan Society for Endoscopic Surgery 2016; 21 (6); 655-810.
Andersen CJ, Murphy KE, Fernandez ML. Impact of Obesity and Metabolic Syndrome on Immunity Adv Nutr. 2016 Jan 15;7(1):66-75.
Cook EJ, Walsh SR, Farooq N, Alberts JC, Justin TA, Keeling NJ. Post-operative neutrophil-lymphocyte ratio predicts complications following colorectal surgery. Int J Surg. 2007; 5:27–30
Vaughan-Shaw PG, Rees JR, King AT. Neutrophil lymphocyte ratio in outcome prediction after emergency abdominal surgery in the elderly. Int J Surg. 2012; 10:157–162
Forget P, Moreau N, Engel H, Cornu O, Boland B, De Kock M, et al. The neutrophil-to-lymphocyte ratio (NLR) after surgery for hip fracture (HF). Arch Gerontol Geriatr. 2015; 60:366–371
Da Silva M, Cleghorn MC, Elnahas A, Jackson TD, Okrainec A, Quereshy FA. Postoperative day one neutrophil-to-lymphocyte ratio as a predictor of 30-day outcomes in bariatric surgery patients. Surg Endosc. 2017 Jun;31(6):2645-2650.
Nozoe T, Ninomiya M, Maeda T, Matsukuma A, Nakashima H, Ezaki T. Prognostic nutritional index: A tool to predict the biological aggressiveness of gastric carcinoma. Surg Today. 2010;40:440–443.
Lee WJ, Almulaifi A, Tsou JJ, Ser KH, Lee YC, Chen SC. Laparoscopic sleeve gastrectomy for type 2 diabetes mellitus: predicting the success by ABCD score. Surg Obes Relat Dis. 2015 Sep-Oct;11(5):991-6.
Brethauer SA, Kim J, el Chaar M, Papasavas P, Eisenberg D, Rogers A, et al; ASMBS Clinical Issues Committee. Standardized outcomes reporting in metabolic and bariatric surgery. Surg Obes Relat Dis. 2015;11(3):489–506.
Felberbauer FX, Langer F, Shakeri-Manesch S, Schmaldienst E, Kees M, Kriwanek et al. Laparoscopic sleeve gastrectomy as an isolated bariatric procedure: intermediate-term results from a large series in three Austrian centers. Obesity Surgery. 2008;18(7):814–818.
D'Hondt M, Vanneste S, Pottel H, Devriendt D, Van Rooy F, Vansteenkiste F. Laparoscopic sleeve gatrectomy as a single procedure for the treatment of morbid obesity and the resulting quality of life, resolution of comorbidities, food tolerance, and 6-year weight loss. Surgical Endoscopy. 2011;25:2498–2504.
Chouillard EK, Karaa A, Elkhoury M, Greco VJ. Laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy for morbid obesity: case-control study. Surgery for Obesity and Related Diseases. 2011;7(4):500–505.
Abbatini F, Capoccia D, Casella G, Coccia F, Leonetti F, Basso N. Type 2 diabetes in obese patients with body mass index of 30–35 kg/m2: sleeve gastrectomy versus medical treatment. Surgery for Obesity and Related Diseases. 2012;8:20–24.
Zhang N, Maffei A, Cerabona T, Pahuja A, Omana J, Kaul A. Reduction in obesity-related comorbidities: is gastric bypass better than sleeve gastrectomy? Surg Endosc. 2013 Apr;27(4):1273-80.
Kashihara H, Shimada M, Yoshikawa K, Higashijima J, Nakao T, Nishi M, et al. Duodenal-jejunal bypass changes the composition of the gut microbiota. Surg Today. 2017 Jan;47(1):137-140.
Ryan KK, Tremaroli V, Clemmensen C, Kovatcheva-Datchary P, Myronovych A, Karns R, et al. FXR is a molecular target for the effects of vertical sleeve gastrectomy. Nature. 2014 May 8;509(7499):183-8.
Seki Y, Kasama K, Hashimoto K. Long-Term Outcome of Laparoscopic Sleeve Gastrectomy in Morbidly Obese Japanese Patients. Obes Surg. 2016 Jan;26(1):138-45.
Gulhane M, Murray L, Lourie R, Tong H, Sheng YH, Wang R, et al. High Fat Diets Induce Colonic Epithelial Cell Stress and Inflammation that is Reversed by IL-22. Sci Rep. 2016 Jun 28;6:28990.
Kashihara H, Shimada M, Yoshikawa K, Higashijima J, Miyatani T, Tokunaga T, et al. Duodenal-Jejunal Bypass Maintains Gut Permeability by Suppressing Gut Inflammation. Obes Surg. 2019 Sep;29(9):2745-2749.
Yoon HY, Kim HN, Lee SH, Kim SJ, Chang Y, Ryu S, et al. Association between Neutrophil-to-Lymphocyte Ratio and Gut Microbiota in a Large Population: a Retrospective Cross-Sectional Study. Sci Rep. 2018 Oct 30;8(1):16031. doi: 10.1038/s41598-018-34398-4.
Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med. 2011 Feb;17(2):179-88.
M Ohta, S Kai, Y Iwashita, Y Endo, T Hirashita, H Eguchi, et al. Initial experience in laparoscopic sleeve gastrectomy for Japanese morbid obesity. Asian J Endosc Surg. 2009;2:68–72.

Download PDF

Reviewer #1 agreed at journal
16 May, 2021
Reviewers invited by journal
28 Dec, 2020
Editor assigned by journal
06 Dec, 2020
Submission checks completed at journal
06 Dec, 2020
Editor invited by journal
06 Dec, 2020
First submitted to journal
04 Dec, 2020

You are reading this latest preprint version

The Impact of the Pre-operative Neutrophil-lymphocyte Ratio as the Predictive Marker of Post-operative Weight Loss and Improving Diabetes in Sleeve Gastrectomy.

Status:

Version 1

Abstract

Figures

Background

Methods

Patient selection and data collection

Technical description of an LSG

NLR, prognostic nutritional index (PNI) and ABCD score

Evaluation of T2DM resolution

Post-operative management

Statistical analysis

Results

Discussion

Conclusions

Acronyms

Declarations

References

Status:

Version 1