|Year : 2020 | Volume
| Issue : 2 | Page : 217-224
Relationship between neutrophil-to-lymphocyte ratio and diabetic neuropathy in type 2 diabetes mellitus
Wagida M.F Abou Raya1, Sally S Abd Elhamed1, Noha H El Salanty2
1 Department of Internal Medicine, Faculty of Medicine (Girls), Al-Azhar University, Cairo, Egypt
2 Department of Internal Medicine, Police Hospital, Nasr City, Egypt
|Date of Submission||18-Feb-2020|
|Date of Decision||29-Feb-2020|
|Date of Acceptance||01-Mar-2020|
|Date of Web Publication||29-Jun-2020|
Sally S Abd Elhamed
MD and Lecturer of Internal Medicine Al-Azhar University, 1Elshazly st. Faisal, Giza, 11222
Source of Support: None, Conflict of Interest: None
Background Diabetic peripheral neuropathy (DPN) is one of the microvascular complications of diabetes mellitus (DM). Several epidemiological studies have shown that inflammation has a central role in the pathogenesis of diabetic complications. Recently, neutrophil-to-lymphocyte ratio (NLR) is considered as a novel marker for inflammation in systemic disease.
Aim To investigate the relationship between the NLR and DPN in type 2 DM, and to estimate whether NLR can be used as a predictive and reliable marker for DPN.
Patients and methods This is a case–control study conducted on 90 individuals; 60 patients with type 2 DM were divided into a group with peripheral neuropathy (DPN) (group 1) and into a group without peripheral neuropathy (group 2) and 30 healthy individuals with age and sex matched served as the control (group 3). All were subjected to full history and clinical examination; laboratory tests included fasting blood glucose, 2 h postprandial, glycated hemoglobin, and renal function tests, estimated glomerular filtration rate. Complete blood count with assessment of NLR, and nerve conduction study.
Results There was highly statistically significant increase in NLR in diabetic patients with peripheral neuropathy in comparison to group without peripheral neuropathy and control group.
Conclusion NLR might be a predictor marker for DPN.
Keywords: diabetic peripheral neuropathy, diabetes mellitus, neutrophil-to-lymphocyte ratio
|How to cite this article:|
Abou Raya WM, Abd Elhamed SS, El Salanty NH. Relationship between neutrophil-to-lymphocyte ratio and diabetic neuropathy in type 2 diabetes mellitus. Sci J Al-Azhar Med Fac Girls 2020;4:217-24
|How to cite this URL:|
Abou Raya WM, Abd Elhamed SS, El Salanty NH. Relationship between neutrophil-to-lymphocyte ratio and diabetic neuropathy in type 2 diabetes mellitus. Sci J Al-Azhar Med Fac Girls [serial online] 2020 [cited 2020 Oct 26];4:217-24. Available from: http://www.sjamf.eg.net/text.asp?2020/4/2/217/288271
| Introduction|| |
Diabetes mellitus (DM) is a systemic disease which has microvascular and macrovascular complications. Microvascular complications include diabetic neuropathy, diabetic nephropathy, and diabetic retinopathy. On the other hand, macrovascular complications include cardiovascular diseases, stroke, and peripheral vascular disease .
The incidence of diabetic peripheral neuropathy (DPN) in type 1 DM was 54–59% while in type 2 diabetes mellitus (T2DM) it was 45% and systemic inflammation was responsible for T2DM complications .
In recent years, the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio, which is derived from a calculation of blood count parameters, were introduced as potential markers of inflammation in cardiac diseases, neoplasm, and diabetes-associated complications . Also, it has been demonstrated as an independent risk factor for a DPN-related pathophysiological process named diabetic microangiopathy, which affects the nutrition supply of neuronal and Schwann cells, causes nerve degeneration, and eventually leads to peripheral neuropathy .
To our knowledge, few studies were found in the literature to discuss the relationship between NLR and DPN.
| Aim|| |
The aim of this study is to investigate the relationship between the NLR in T2DM with peripheral neuropathy (DPN), and to estimate whether NLR can be used as a reliable marker.
| Patients and methods|| |
This case–control study was conducted on 90 Egyptian patients, 30 diabetic patients with peripheral neuropathy and are considered group 1 and 30 diabetic patients without peripheral neuropathy on clinical bases considered group 2 and 30 apparently healthy volunteers as controls considered group 3. They were selected during the period from December 2018 and November 2019. This study was conducted at Al-Zahraa University Hospital and Police Hospital Nasr City. An informed consent was obtained from all patients. Also, approval of ethics committee of Faculty of Medicine, Al-Azhar University was obtained. Diabetes was diagnosed based on the WHO consulting criteria .
DPN was defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes. Combinations of more than one following tests have more than 87% sensitivity in detecting DPN: pinprick, temperature, and vibration perception (using a 128-Hz tuning fork), 10-g monofilament pressure sensation at the distal hallux and ankle reflexes .
Patients with T2DM with or without diabetic neuropathy.
Patients excluded from the study were those with diabetic ketoacidosis, hyperosmolar nonketotic coma, heart failure, ischemic heart disease, local causes that affect the nerves, autoimmune disease, chronic kidney disease, hematological disease, thyroid disease, blood transfusion during past 2 weeks, patient receiving steroids or immunosuppressants, patients with infection, or macrocytic anemia and suspecting vitamin B12 deficiency with peripheral neuropathy.
All patients underwent a thorough assessment of history, complete clinical examination, laboratory investigations including complete blood count, fasting blood glucose, 2 h postprandial, glycated hemoglobin (HbA1c), serum transaminases (ALT–AST), blood urea and serum creatinine, serum uric acid, estimated glomerular filtration rate, lipid profile, thyroid-stimulating hormone, high-sensitive C-reactive protein (HS-CRP), and nerve conduction study.
Results were statistically analyzed using the Statistical Package for the Social Sciences (SPSS, 22.0, IBM/SPSS Inc., Chicago, IL, USA). Descriptive and analytical statistics by the following test: Pearson’s χ2 test and Fisher’s exact test which were used to compare between two or more groups regarding one qualitative variable.
Analysis of variance was used for continuous data to test for significant difference between more than two normally distributed groups. Also, Kruskal–Wallis tests: used for nonparametric data and post-hoc test was used after significant Kruskal–Wallis test.
Correlation analyses were done by Spearman’s rank correlation coefficient (r’s). Test characteristics were estimated by receiver operating characteristic (ROC) curve and included the best cutoff value, area under the curve, its SE, and P value. To assess the effectiveness of the test, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated at the optimal cutoff.
In all applied tests, P values more than or equal to 0.05 are statistically nonsignificant, P values less than 0.05 are significant, and P values less than 0.01 are highly significant.
| Results|| |
The study was conducted on 90 participants, 35 (53.3%) women and 45 (46.7%) men. There were no significant differences in demographic data between the three studied groups. Laboratory findings are shown in [Table 1], which revealed highly significant difference in fasting blood glucose, 2 h postprandial, HbA1c, triglycerides, high-density lipoprotein, low-density lipoprotein, and HS-CRP in both diabetic groups ([Table 1]).
|Table 1 Comparison between type 2 diabetes mellitus with peripheral neuropathy (group 1), type 2 diabetes mellitus without neuropathy (group 2), and control group (group 3) regarding biochemical parameters|
Click here to view
As regards neurological tests [vibration test vibrations perception threshold (VPT), pinprick test, ankle reflex test, nerve conduction test), there were highly significant difference between patients with DPN (group 1) and diabetic patients without peripheral neuropathy (group 2) and the control group(group 3) ([Table 2]).
|Table 2 Comparison between type 2 diabetes mellitus with peripheral neuropathy, type 2 diabetes mellitus without neuropathy and control groups regarding neurological tests|
Click here to view
As regards, neutrophil and lymphocyte counts there was statistically highly significant difference between the DPN group and the control group in the neutrophil count and significant difference in lymphocyte count (P<0.001 and 0.022, respectively). The median NLR in the diabetic neuropathic patients was 2.44, while in the diabetic group without peripheral neuropathy was 1.92 and in the control group was 1.4 with high statistically significant difference between the three studied groups and the highest percentage was detected in the neuropathy group ([Table 3]).
|Table 3 Comparison between type 2 diabetes mellitus with peripheral neuropathy, type 2 diabetes mellitus without neuropathy, and control groups regarding neutrophil–lymphocyte ratio|
Click here to view
There were significant positive correlation between NLR and VPT in the DPN group (r=0.39, P=0.03) ([Figure 1]) and highly significant positive correlation between NLR and HS-CRP (r=0.49, P=0.006) ([Figure 2]) and also HbA1c in the same group (r=0.46, P=0.011) ([Figure 3]).
|Figure 1 Positive correlation between NLR and VPT in group 1 (DPN) versus group 2 (T2DM). DPN, diabetic peripheral neuropathy; NLR, neutrophil-to-lymphocyte ratio; T2DM, type 2 diabetes mellitus; VPT, vibrations perception threshold.|
Click here to view
|Figure 2 Positive correlation between NLR and HS-CRP in group 1 (DPN) versus group 2 (T2DM). DPN, diabetic peripheral neuropathy; HS-CRP, high-sensitive C-reactive protein; NLR, neutrophil-to-lymphocyte ratio; T2DM, type 2 diabetes mellitus.|
Click here to view
|Figure 3 Positive correlation between NLR and HbA1c in group 1 (DPN) versus group 2 (T2DM). DPN, diabetic peripheral neuropathy; HbA1c, glycated hemoglobin; NLR, neutrophil-to-lymphocyte ratio; T2DM, type 2 diabetes mellitus.|
Click here to view
According to nerve conduction studies, our study showed 28 patients with peripheral neuropathy (DPN) and 32 patients without peripheral neuropathy whose were divided into tertiles based on NLR values. Tertiles were defined as NLR less than or equal to 1.50 (low) (n=9), NL more than 1.50 less than or equal to 2.18 (medium) (n=22), and NLR more than 2.18 (high) (n=29). Percentages of positive nerve conduction status showed a highly significant association (P<0.001) with the highest NLR tertile group ([Table 4]).
|Table 4 Association between nerve conduction status and neutrophil-to-lymphocyte ratio bases on tertiles value in diabetic patients with or without peripheral neuropathy|
Click here to view
In our study, the sensitivity, specificity, and the analysis by ROC curve showed that the area under the ROC curve was 0.70 (P≤0.007) with the best cutoff point of NLR to differentiate between DPN and T2DM without neuropathy groups being 1.58 with 100% sensitivity, 40% specificity, 62.5% PPV, 100% NPV, and 70% accuracy. The best cutoff point of NLR to differentiate between DPN and control groups was 1.59 with 100% sensitivity, 96.7% specificity, 88.2% PPV, 100% NPV, and 93.3% accuracy and the area under the ROC curve was 0.98 (P≤0.001). Also, the best cutoff point of NLR to differentiate between T2DM without neuropathy and control groups was 1.84 with 56.7% sensitivity, 86.7% specificity, 94.4% PPV, 69% NPV, and 76.7% accuracy and the area under ROC curve was 0.74 (P≤0.001) ([Table 5], [Figure 4]).
|Table 5 Diagnostic performance and test characteristics of neutrophil-to-lymphocyte ratio at the best cutoff value detected by Youden index|
Click here to view
|Figure 4 Receiver operating characteristic curves of NLR for pairwise discrimination between the three studied groups. NLR, neutrophil-to-lymphocyte ratio.|
Click here to view
| Discussion|| |
T2DM and its vascular complications had been proposed to inflammation, immune dysfunction, and hypercoagulability. Also, many endothelial, inflammatory procoagulant biomarkers increased in microvascular and macrovascular diabetic complications including nephropathy and cardiovascular complications such as interleukin-6 and tumor necrosis factor-α .
Peripheral blood is considered as the mirror of chronic inflammation through the numbers and ratio of immune-related cells. White blood cell count and its subtypes are potential predictors and markers of inflammation. The NLR and the platelet-to-lymphocyte ratio, which derive from a calculation of blood count parameters were introduced as valuable markers of inflammation to predict morbidity and mortality in cardiac diseases, neoplasm, and diabetes-associated complications ,,.
The pathogenesis of DPN is so complex that it remains to be explored. Research has shown that early microvascular disorders and inflammatory processes play important roles in the occurrence and development of DPN ,,.
Our study showed that most of the studied variables revealed significant difference between the studied groups except cholesterol, thyroid-stimulating hormone, and BMI. This came in agreement with many studies ,,,.
Regarding neutrophil and lymphocyte counts, the neutrophils were significantly higher in the neuropathic group with mean 2.44 than other groups. Also, there was statistically significant difference in lymphocyte count with mean 1.75 in the neuropathic group which is lower than the group of DM without neuropathy 2.14 and control group 2.36. The median NLR in the control group was 1.4, in the diabetic group without neuropathy was 1.92 and in the neuropathic pain was 2.44 with high statistically significant difference between the three studied groups and the highest percentage was detected in the neuropathy group. These results are in agreement with Xu and colleagues who reported that the mean neutrophil level in the diabetic without neuropathy was 3.80±1.23, while in the group with neuropathy the level was higher 4.04±1.05 with statistically significant difference between the two groups. Also, they reported that the mean lymphocyte level was 1.84±0.75 in the diabetic patient group without neuropathy and was lower in the group with neuropathy (1.61±0.47). Xu et al.  also reported that NLR was higher in the DPN group compared with those without neuropathy (2.58±0.50 vs. 2.18±0.61, P<0.001).
This is also in agreement with the results of Fawwad et al. , where the NLR was 1.14 times higher in diabetic patients with at least one microvascular complication as compared with diabetic patients without any complications (4.34±3.32 vs. 3.36±2.67, P<0.0001).
Similarly, in an Egyptian study diabetic patients with microvascular complications were having higher NLR in comparison to diabetic patients without complications and control group (P<0.001) .
In our study, according to nerve conduction study, the positive diabetic patients with neuropathy were 28 and without neuropathy were 32 who were divided into tertiles based on NLR values. The first (low) were defined as NLR less than or equal to 1.50 (n=9), second (medium) as NLR more than 1.50 less than or equal to 2.18 (n=22), and the third (high) tertiles with NLR more than 2.18 (n=29). Percentages of positive nerve conduction status showed a highly significant association (P<0.001) with the highest NLR tertile group.
Also, we found significant positive correlation between NLR and VPT in the DPN group (r=0.39, P=0.03) and highly significant positive correlation between NLR and both HS-CRP (r=0.49, P=0.006) and HbA1C r (r=0.46, P=0.011) in the same group. This finding was similar to the results of a study by Moursy et al.  comparing peripheral diabetic neuropathy and diabetic patients with normal test findings, NLR values were higher in patients who had abnormal monofilament test (P=0.023), those who had VPT of more than 25 v (P=0.005) and patients with absent ankle reflex (P=0.011). Fawwad et al.  also reported a significant correlation between NLR and HbA1c.
In our study analysis of the ROC curve showed that the area under the ROC curve was 0.70 (P≤0.007) with the best cutoff point of NLR to differentiate between DPN and T2DM groups was 1.58 with 100% sensitivity, 40% specificity, 62.5% PPV, 100% NPV, and 70% accuracy. Similar results were revealed by Liu et al.  who revealed the effect of NLR on making the diagnosis of DPN analyzed by the ROC curve.
DPN pathogenesis involves complex molecular networks and processes as it is considered a low-grade chronic subclinical inflammation, thus there is strong association between inflammation and DPN . NLR reflects the balance between neutrophils and lymphocytes in the body, which represents the connection between the ongoing inflammation and the immune-regulatory pathways ,. These could be partly explaining why NLR could be a predictor of DPN and reflect the abnormality of nerve conduction velocities and VPT results.
Although the results obtained from this study is promising, there were some limitations such as it is a single-center study and the relatively small sample size.
| Conclusion|| |
T2DM patients with higher NLR levels are more likely to develop DPN and NLR might be a predictive marker for DPN.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Abdallah AI, Abdelaziz AA, El-Sayed El-Meghawry EL, Emran TM. Study of neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) as a predictor inflammatory marker for diabetic nephropathy in type 2 diabetic patients. Egypt J Hosp Med
Mohammad WH, Ahmad AB, Al-Maghraby MH, Abdelrhman MZ, Ezzate S. Is neutrophil-lymphocyte ratio a novel biomarker for macrovascular and microvascular complications of type 2 diabetes? Egypt J Inter Med
Mendes BB, Oliveira AC, Alcântara KC. Comparison of the neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios in normoglycemic and hyperglycemic subjects. Einstein (São Paulo)
Vural G, Gümüsyayla S. Monocyte-to-high density lipoprotein ratio is associated with a decreased compound muscle action potential amplitude in patients with diabetic axonal polyneuropathy. Medicine
Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: provisional report of a WHO consultation. Diabetic Med
Korean Diabetes Association. Treatment guideline for diabetes. J Korean Diabetes
Navarro JF, Mora C. Role of inflammation in diabetic complications. Nephrol Dial Transplant
Mete Ural Ü, Şehitoğlu İ, Bayoğlu Tekin Y, Kir Şahin F. Neutrophil‐to‐lymphocyte and platelet‐to‐lymphocyte ratios in patients with endometrial hyperplasia and endometrial cancer. J Obstetr Gynaecol Res
Zhou B, Zhan C, Wu J, Liu J, Zhou J, Zheng S. Prognostic significance of preoperative Neutrophil-to3Lymphocyte ratio in surgically resectable pancreatic neuroendocrine tumors. Med Sci Monitor
Liu S, Zheng H, Zhu X, Mao F, Zhang S, Shi H et al.
Neutrophil-to-lymphocyte ratio is associated with diabetic peripheral neuropathy in type 2 diabetes patients. Diabet Res Clin Pract
Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C et al.
Vascular risk factors and diabetic neuropathy. N Engl J Med
Vincent AM, Callaghan BC, Smith AL, Feldman EL. Diabetic neuropathy: cellular mechanisms as therapeutic targets. Nat Rev Neurol
Kampoli AM, Tousoulis D, Briasoulis A, Latsios G et al.
Potential pathogenic inflammatory mechanisms of endothelial dysfunction induced by type 2 diabetes mellitus. Curr Pharmac Design
Moursy EY, Megallaa MH, Mouftah RF, Ahmed SM. Relationship between neutrophil lymphocyte ratio and microvascular complications in Egyptian patients with type 2 diabetes. Am J Intern Med
Xu T, Weng Z, Pei C, Yu S, Chen Y, Guo W et al.
The relationship between neutrophil-to-lymphocyte ratio and diabetic peripheral neuropathy in type 2 diabetes mellitus. Medicine
Fawwad A, Butt AM, Siddiqui IA, Khalid M, Sabir R, Basit A. Neutrophil-to-lymphocyte ratio and microvascular complications in subjects with type 2 diabetes: Pakistan’ s perspective. Turk J Med Sci
Rajakariar R, Lawrence T, Bystrom J, Hilliard M, Colville-Nash P, Bellingan G et al.
Novel biphasic role for lymphocytes revealed during resolving inflammation. Blood
El KD, Filep JG. Targeting neutrophil apoptosis for enhancing the resolution of inflammation
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]