|Year : 2020 | Volume
| Issue : 3 | Page : 275-279
Relation between the novel marker monocyte to high-density lipoprotein cholesterol ratio and severity in multiple sclerosis
Ersin Kasim Ulusoy, Ömer Faruk Bolattürk, Mehmet Fatih Göl
Department of Neurology, Kayseri Training and Research Hospital, Kayseri, Turkey
|Date of Submission||04-May-2019|
|Date of Acceptance||31-May-2019|
|Date of Web Publication||10-Jun-2020|
Dr. Ersin Kasim Ulusoy
Department of Neurology, Kayseri Training and Research Hospital, Seker Mahallesi, Molu Yolu/Kocasinan, 38010, Kayseri
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: This study aimed to establish whether there is a relationship between the Monocyte to High-Density Lipoprotein Cholesterol (HDL-C) ratio (MHR) and severity of disease, and whether it can be used as a new marker for predicting disability in Multiple Sclerosis (MS), a chronic disease, which is usually contracted in early adolescence. Methods: 184 patient subjects who had been definitively diagnosed with MS, based on the McDonald criteria, and 105 healthy subjects with a similar age and gender profile were included in the study. The patients' Expanded Disability Status Scale (EDSS) scores, MS subtypes, length of time with the disease and demographics were captured. Blood samples were collected for hematologic and biochemical testing. The MHR values were calculated and statistically compared with those of the control group. Results: The average age of the MS patients was 38.3 ± 8.6 years and their average EDSS score was 2.5 [0-7.5]. The patient arm consisted of 118 (64.1%) females and 66 (35.9%) males. In the patients with MS, the MHR was 15.01 ± 0.63 compared to 9.61 ± 0.25 in the controls. This difference was statistically significant (P < 0.001). In the MS patients, the MHR cut-off value was 12.95 compared to controls, which was statistically significant (P < 0.001). Also, a statistically-significant (r: 0.297, P < 0.001) positive correlation was found between the MHR and EDSS score. Conclusion: The Monocyte to High-Density Lipoprotein Cholesterol ratio is associated with disease severity and disability in MS patients, and may be used as an independent marker for predicting disability. However, broader-scale studies are needed for more conclusive results.
Keywords: Disability, high-density lipoprotein, inflammation, monocyte, multiple sclerosis
|How to cite this article:|
Ulusoy EK, Bolattürk &F, Göl MF. Relation between the novel marker monocyte to high-density lipoprotein cholesterol ratio and severity in multiple sclerosis. Ann Indian Acad Neurol 2020;23:275-9
|How to cite this URL:|
Ulusoy EK, Bolattürk &F, Göl MF. Relation between the novel marker monocyte to high-density lipoprotein cholesterol ratio and severity in multiple sclerosis. Ann Indian Acad Neurol [serial online] 2020 [cited 2022 Sep 30];23:275-9. Available from: https://www.annalsofian.org/text.asp?2020/23/3/275/263998
| Introduction|| |
Multiple Sclerosis (MS) is an autoimmune, inflammatory, demyelinating and neurodegenerative disease, marked by episodes of relapsing neurological dysfunction, usually affecting females. MS is the leading cause of neurologic disability affecting the younger age groups in developed countries.
MS is characterized by disruption of the blood-brain barrier (BBB) due to lesions occurring in the white matter, and migration of immune reactive cells to the disturbed region, which target and damage oligodendrocytes and myelin sheaths. The etiology of the disease is thought to principally involve the peripheral activation of Th1 lymphocytes which traffic to the central nervous system and react with myelin autoantigens., However, it has been recently shown that monocytes and macrophages originating from myeloid cells play a crucial role in the secretion of proinflammatory and prooxidant cytokines which exacerbate immune response in MS.,
The blood-brain barrier is a selective and dynamic barrier that has a major role in maintaining brain homeostasis. It is composed by specialized brain endothelial cells which are firmly connected via adherent and tight junctions. Previous studies have shown that oxidative and inflammatory events contribute to endothelial dysfunction in MS patients. It has been shown that high-density lipoprotein cholesterol (HDL-C) protects endothelium against the adverse effects of low-density lipoprotein (LDL-C) and the oxidation caused by LDL-C molecules., For this reason, it was believed that HDL-C exhibits anti-inflammatory and antioxidant properties. It has been shown that increased monocyte count and decreased HDL-C levels may be related to inflammation and oxidative stress., Recently, the monocyte count to HDL-C ratio (MHR) is increasingly recognized as a novel clinically-relevant biomarker of pathological inflammation and a new predictor and prognostic factor., Moreover they are inexpensive and readily available components of the standard complete blood count (CBC). However, to the best our knowledge, no studies have thus far investigated MHR in MS patients. Our study was the first of its kind in this respect.
This study aimed to establish whether there is a relationship between the MHR and severity of disease, and whether it can be used as a new marker for predicting disability in Multiple Sclerosis (MS), a chronic disease, which is usually contracted in early adolescence.
| Methods|| |
Study population and design
Patients who had been definitively diagnosed with MS based on the McDonald criteria between September 2018 and March 2019 and who were not having an episode of relapse were randomized and prospectively included in the study. The diagnosis of MS, identification of the clinical form of the disease, and its outpatient monitoring were made at the MS Outpatient Clinic, Neurology Ward, Kayseri City Hospital. The study was approved by the local ethics committee and conducted according to the Declaration of Helsinki. Consent was received from all subjects.
Patients' age, gender, length of time with the disease, medications being used, neurological systems affected in the clinical course, neurological examination findings, duration of follow-up, and clinical form were captured. The Expanded Disability Status Scale (EDSS) scores were used to evaluate the functional status of MS patients. Subjects with an EDSS score between 0 and 3.5 were classified as having mild-moderate MS, and those having an EDSS score between 4 and 10 were classified as having severe MS.
Healthy subjects were selected among healthy individuals with a similar age and gender profile who visited the check-up service at our hospital and presented with no sign of a neuropsychiatric, systemic, metabolic, infective or inflammatory condition.
The exclusion criteria included heart failure, renal or hepatic failure, active hepatobiliary disease, active infectious disease, chronic inflammatory or immunologic conditions, hematological diseases, malignancy, and immunological disease, smoking or alcohol use, immunosuppressive drug use, receiving an antiinflammatory drug over the past 10 days, known adrenal or metabolic conditions, individuals younger than 18 years or older than 50 years of age, or receiving treatment with a systemic medication that could affect hematological parameters, such as antihyperlipidemic therapy.
In our hospital, blood samples were routinely drawn from the antecubital vein at 08.00 to 10.00 am after an overnight fasting period. After performing the comprehensive neurologic examinations, we measured the blood lipid profiles, hematology profiles, and C-reactive protein (CRP) levels of participants. The other biochemical analyses were determined by standard methods. We calculated MHR as the ratio of the monocyte count to the level of HDL and the neutrophil-to-lymphocyte ratio (NLR) as the ratio of the neutrophil count to the lymphocyte count.
The software package IBM SPSS for Windows Version 22.0 was used for statistical analysis. Numerical variables were summarized by mean ± standard deviation or median [min-max] values, and categorical variables by numbers and percentages. Parametric test assumptions (normality and homogeneity of variance) were checked before comparing the groups for numerical variables. Normal distribution of the numerical variables was verified by the Shapiro Wilks test. The homogeneity of variance for the compared groups was examined using the Levene test. The presence of difference between 2 independent groups in terms of the numerical variables was examined in independent groups using the t test, if parametric test conditions were met, or using the Mann Whitney U test, if the conditions were unmet. Welch ANOVA was used for comparing more than 2 independent groups. The difference between the groups in terms of categorical variables was examined using the Chi-square test. The relationship between the numerical variables was given with the Pearson or Spearman correlation coefficients. The MHO value separating the study group and the controls was determined using ROC curve analysis. The level of significance was taken as P < 0.05.
| Results|| |
A total of 184 MS patients and 105 healthy subjects were included in the study. Baseline clinical characteristics, disease properties, and laboratory parameters of subjects are shown in [Table 1] and [Table 2]. There was no statistically significant difference between the study groups in terms of age, sex, neutrophils, lymhocycte, LDL-C, total platelet count, creatinine, white blood cell count, triglyceride, glucose, hsCRP, ESR, and NLR levels. MHR and monocyte levels were significantly higher, and HDL-C and hemoglobin levels significantly lower in patients with MS than in controls.
|Table 2: Monocyte-to-high density lipoprotein ratio (MHR) and neutrophil-to-lymphocyte ratio (NLR) in patients with MS|
Click here to view
The MHR levels was statistically significantly high in the MS patients compared to controls, whereas the NLR ratio was higher in the patient subjects compared to controls, although not to a statistically significant degree (P < 0.001 and P = 0.802, respectively) [Table 2].
The MHR ratio was statistically significantly higher in patients who were classified as having severe disease, as determined based on the EDSS scores, compared to those with mild or moderate disease (P = 0.005). The MHR ratio was also statistically significantly higher in patients with SPMS or PPMS with highly active disease, compared to other disease subtypes (P < 0.001) [Table 3].
A statistically significant correlation was detected between the MHR levels and the neutrophil and triglyceride levels, whereas no such correlation could be found with other laboratory levels. Based on the clinical parameters, the MHR levels statistically significantly increased with longer time with disease and higher EDSS score (P = 0.027 and P ≤ 0.001, respectively) [Table 4].
|Table 4: Correlation analysis between MHR and other laboratory and clinic data among patients with MS|
Click here to view
The ROC analysis was performed to determine the MHR cutoff value (>12.95) for predicting significance in MS patients. The sensitivity value was taken as 63.6.%, the specificity value as 92.4%, and the area under the ROC curve value as 0.76 [Figure 1].
| Discussion|| |
This prospective study investigated whether any correlation existed between the MHR level, which is considered as an inflammation marker in MS patients, and the disability score, prognosis, demographics and clinical variables. We found that the MHR levels were statistically higher than in the healthy controls. Moreover, this difference increased with higher EDSS scores, gaining statistical significance in the progressive forms of the disease. To the best of our knowledge, this study is the first of its kind, demonstrating the relationship between MHR and disease severity in patients with MS.
The basic pathological characteristics of the central nervous system (CNS) tissues in MS patients provide a clue for the pathogenesis, although the etiology of MS has not yet been completely understood. Clinicians have been investigating markers that can serve as a direct or indirect predictor of inflammation and oxidative stress, which play a major role in MS pathology and in predicting disease prognosis. Several studies have reported elevated levels of oxidative stress and inflammation markers such as platelet/lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), HLA genotype, chitinase 3-like 1, Vascular Endothelial Growth Factor Receptor 2, and monocyte/lymphocyte ratio (MLR) in patients with MS.,, Nevertheless, a definitive biomarker indicating diagnosis and activity of MS is yet to be discovered.
Monocytes are considered to be a subtype of leukocytes, which play an important role in inflammation. Activated monocytes interact with damaged or activated brain endothelium. This leads to overexpression of some proinflammatory mediator molecules including interleukin (IL)-1, and IL-6, tumor necrosis factor -α, transforming growth factor -α and -β, platelet-derived endothelial cell growth factor macrophage colony-stimulating factor, and insulin-like growth factor., After this, monocytes differentiate into the macrophages that eventually ingest oxidized LDL-C and form the initial foamy cells.,, Contrarily, HDL-C molecules counteract macrophage migration and remove cholesterol debris from those cells. Recent studies also indicate the role of HDL-C in modulating monocyte activation, adhesion, and also in controlling the proliferation of progenitor cells that differentiate to monocytes. Besides its anti-inflammatory and antioxidative effects, HDL-C molecules also increase endothelial nitric oxide synthase expression.,, Therefore, monocytes exert a proinflammatory and prooxidant effects, but HDL-C functions as a reversal factor during these processes. Given those findings and our results, we suggest that MHR is a better indicator of systemic inflammation than other hematological parameters in inflammatory disorders, largely because MHR indicates the balance of proinflammatory and anti-inflammatory reactions.
Despite all advances, predicting disease prognosis in MS remains difficult, as different neuro-inflammatory mechanisms act in individual patients. Açıkgöz et al. in patients with Behçet's Disease and Köseoǧlu et al. in patients with OSAS have found the MHR values to be high, and concluded that it might be associated with systemic inflammation and endothelial dysfunction., However, in none of the previous studies had MHR, a recently-recognized marker of chronic inflammation, been associated with the disability score, an indicator of inflammation severity in MS patients. In this study, the contribution of the MHR level to the change in disability was significant, and patients with higher baseline MHR experienced greater worsening of EDSS scores. A similar relationship also existed between the length of time with disease and the MHR level. Higher MHR levels were strongly correlated with the progressive forms of MS.
Our study had several limitations. Firstly, it was carried out at a single center, and the number of patients included was relatively small. Secondly, the serum HDL-C levels and complete blood monocyte count were variable over time, and measurement at a single time point in our study may not be fully representative of the serum levels. Thirdly, all of the patients were using disease-modifying treatments, which may affect blood leukocyte levels and thus the results.
| Conclusion|| |
Altogether, inflammation seems to play an important role in MS. Our results have shown that MHR levels, an indicator of the degree of inflammation, is related with the disease severity and disability in MS, and an independent marker for predicting disability. We suggest that the MHR levels are a useful, practical, cheap and easily-calculable marker for predicting disability in MS. Our study is the first of its kind to demonstrate this relationship. Nevertheless, broader-scale, randomized studies are needed to establish clearer results and elucidate the pathophysiology.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Marrie RA, Yu N, Blanchard JF, Leung S, Elliott L. The rising prevalence and changing age distribution of multiple sclerosis in Manitoba. Neurology 2010;74:465-71.
Friese MA, Fugger L. Pathogenic CD8 T cells in multiple sclerosis. Ann Neurol 2009;66:132-41.
Hemond CC, Glanz BI, Bakshi R, Chitnis T, Healy BC. The neutrophil-to-lymphocyte and monocyte-to-lymphocyte ratios are independently associated with neurological disability and brain atrophy in multiple sclerosis. BMC Neurol 2019:23;1-10.
Hemmer B, Kerschensteiner M, Korn T. Role of the innate and adaptive immune responses in the course of multiple sclerosis. Lancet Neurol 2015;14:406-19.
Khaibullin T, Ivanova V, Martynova E, Cherepnev G, Khabirov F, Granatov E, et al
. Elevated levels of proinflammatory cytokines in cerebrospinal fluid of multiple cclerosis patients. Front Immünol 2017;8:1-10.
Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med 2013;19:1584-596.
Canpolat U, Çetin EH, Cetin S, Aydin S, Akboga MK, Yayla C, et al.
Association of monocyte-to HDL cholesterol ratio with slow coronary flow is linked to systemic inflammation. Clin Appl Thromb Hemost 2016;22:476-82.
Uslu AU, Sekin Y, Tarhan G, Canakcı N, Gunduz M, Karagulle M. Evaluation of monocyte to high-density lipoprotein cholesterol ratio in the presence and severity of metabolic syndrome. Clin Appl Thromb Hemost 2018;24:828-33.
Palavra F, Marado D, Mascarenhas-Melo F, Sereno J, Teixeira-Lemos E, Nunes CC, et al
. New markers of early cardiovascular risk in multiple sclerosis patients: Oxidized-LDL correlates with clinical staging. Dis Markers 2013;34:341-48.
Koseoglu HI, Pazarli AC, Kanbay A, Demir O. Monocyte count/HDL cholesterol ratio and cardiovascular disease in patients with obstructive sleep apnea syndrome: A multicenter study. Clin Appl Thromb Hemost 2018;24:139-44.
Stokes KY, Calahan L, Hamric CM, Russell JM, Granger DN. CD40/CD40L contributes to hypercholesterolemia-induced microvascular inflammation. Am J Physiol Heart Circ Physiol 2009;296:689-97.
Burger D, Dayer JM. High-density lipoprotein-associated apolipoprotein A-I: The missing link between infection and chronic inflammation? Autoimmun Rev 2002;1:111-7.
Kurtzke JF. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 1983;33:1444-52.
Frohman EM, Racke MK, Raine CS. Multiple sclerosis the plaque and its pathogenesis. N
Engl J Med 2006;354:942-55.
Lysandropoulos AP, Mavroudakis N, Pandolfo M, et al.
HLA genotype as a marker of multiple sclerosis prognosis: A pilot study. J Neurol Sci 2017;375:348-54.
Modvig S, Degn M, Roed H, Sørensen TL, Larsson HB, Langkilde AR, et al.
Cerebrospinal fluid levels of chitinase 3-like 1 and neurofilament light chain predict multiple sclerosis development and disability after optic neuritis. Mult Scler 2015;21:1761-70.
Kouchaki E, Tamtaji OR, Dadgostar E, Karami M, Nikoueinejad H, Akbari H. Correlation of serum levels of IL-33, IL-37, soluble form of vascular endothelial growth factor receptor 2 (VEGFR2), and circulatory frequency of VEGFR2-expressing cells with multiple sclerosis severity. Iran J Allergy Asthma Immunol 2017;16:329-37.
Harris VK, Tuddenham JF, Sadiq SA. Biomarkers of multiple sclerosis: Current findings. Degener Neurol Neuromuscul Dis 2017;7:19-29.
Jensen J, Krakauer M, Sellebjerg F. Cytokines and adhesion molecules in multiple sclerosis patients treated with interferon-B 1b. Cytokine 2005;29:24-30.
Savarin C, Hinton DR, Valentin-Torres A, Chen Z, Trapp BD, Bergmann CC, et al.
Astrocyte response to IFN-γ limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis. J Neuroinflammation 2015;12:79.
Spencer JI, Bell JS, DeLuca GC. Vascular pathology in multiple sclerosis: Reframing pathogenesis around the blood-brain barrier. J Neurol Neurosurg Psychiatry 2017;0:1-11.
Alvarez JI, Cayrol R, Prat A. Disruption of central nervous system barriers in multiple sclerosis. Biochim Biophys Acta 2011;1812:252-64.
Weinstock-Guttman B, Zivadinov R, Mahfooz N, Carl E, Drake A, Schneider J, et al.
Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. J Neuroinflammation 2011;127:1-7.
Yvan-Charvet L, Pagler T, Gautier EL, Avagyan S, Siry RL, Han S, et al
. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 2010;328:1689-93.
Murphy AJ, Woollard KJ. High-density lipoprotein: A potent inhibitor of inflammation. Clin Exp Pharmacol Physiol 2010;37:710-18.
Kuvin JT, Patel AR, Sidhu M, Rand WM, Sliney KA, Pandian NG, et al
. Relation between high-density lipoprotein cholesterol and peripheral vasomotor function. Am J Cardiol 2003;92:275-79.
Tomassini V, Fanelli F, Prosperini L, Cerqua R, Cavalla P, Pozzilli C. Predicting the profile of increasing disability in multiple sclerosis. Mult Scler J 2018;24:1-10.
Acikgoz N, Kurtoǧlu E, Yagmur J, Kapicioglu Y, Cansel M, Ermis N. Elevated monocyte to high-density lipoprotein cholesterol ratio and endothelial dysfunction in Behçet disease. Angiology 2017;68:1-6.
[Table 1], [Table 2], [Table 3], [Table 4]
|This article has been cited by|
||Monocyte to High-Density Lipoprotein Ratio: A Novel Predictive Marker of Disease Severity and Prognosis in Patients With Neuromyelitis Optica Spectrum Disorders
| ||Jinwei Zhang, Yanfei Li, Yongyan Zhou, Kaixin Wang, Chunyang Pan, Yi Zhao, Haojie Xie, Ranran Duan, Zhe Gong, Yanjie Jia |
| ||Frontiers in Neurology. 2021; 12 |
|[Pubmed] | [DOI]|