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Association of copeptin and cortisol in newly diagnosed multiple sclerosis patients

Journal of Neuroimmunology, pages 21 - 24

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system. Obesity may increase the risk of developing MS. The aim of this study was to evaluate copeptin and cortisol plasma levels in newly diagnosed untreated MS patients and to determine whether copeptin and cortisol are related to the patients' clinical statuses. We report that copeptin and cortisol were higher in overweight/obese MS patients. Positive correlations were observed between the two parameters. We conclude that alterations of copeptin and cortisol levels in multiple sclerosis patients may be related to adiposity. An increase in cortisol may also be associated with copeptin secretion.

Highlights

 

  • We examined copeptin and cortisol levels in multiple sclerosis (MS) patients.
  • Plasma copeptin and cortisol were higher in overweight/obese MS subjects.
  • Alterations of copeptin and cortisol in MS may be related to adiposity.
  • Significant positive correlations were found between copeptin and cortisol in MS.
  • A rise in cortisol in MS may be associated with copeptin secretion.

Keywords: Multiple sclerosis, Copeptin, Cortisol, Adiposity.

1. Introduction

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that results in neurodegeneration and demyelination ( Compston and Coles, 2002 ). Because the majority of patients affected are young adults, MS may be the most common cause of nontraumatic disability in this group. The exact etiology of MS is still not known. However, it has been suggested that obesity may increase the risk of developing MS; this thesis was supported by cohort studies (Munger et al, 2009 and Wesnes et al, 2014). From a pathological point of view, MS is characterized by central nervous system inflammation, demyelination, axonal injury and axonal loss ( Kamm et al., 2014 ).

Several studies indicated the role of copeptin as an inflammation marker and as a prognostic factor of the outcome in different diseases, including those originating as damage to the brain (Dobsa and Edozien, 2013, Katan et al, 2009, and Katan and Christ-Crain, 2010). Copeptin is a 39-amino acid peptide first described by Holwerda in 1972 ( Holwerda, 1972 ). Copeptin, arginine–vasopressin (AVP) and neurophysin II originate from the same precursor, the 164-amino acid polypeptide preprovasopressin ( Land et al., 1982 ). Copeptin comprises the C-terminal part of the AVP precursor (CT-proAVP). Vasopressin and copeptin exert their biological effects by binding to tissue-specific G-protein-coupled receptors, including V1a receptors that mediate arteriolar vasoconstriction, V2 receptors that cause antidiuretic effects, and V1b receptors that are found on adenohypophysis and pancreatic islet cells and promote the secretion of ACTH and insulin, respectively (Birnbaumer, 2000 and Holmes et al, 2004). Copeptin is secreted in an equimolar ratio to AVP. Copeptin is stable and therefore easy to measure in plasma. Copeptin's levels closely reflect the production of AVP (Morgenthaler et al, 2006 and Katan and Christ-Crain, 2010).

It has been reported that corticotrophin-releasing hormone (CRH) and vasopressin that are released from the paraventricular nuclei of the hypothalamus enhance the secretion of adrenocorticotrophic hormone (ACTH) from pituitary corticotrophs. Next, in turn, ACTH stimulates glucocorticoid secretion from the adrenal ( Uchoa et al., 2014 ). This hormonal cascade is initiated by different types of stressors ( Katan and Christ-Crain, 2010 ). Thus, copeptin, which is a strong stimulator of ACTH release, may be a good marker of hypothalamo-pituitary–adrenal (HPA) activity.

Previously published data indicate that disturbed HPA axis activity has been observed in MS patients (Kumpfel et al, 2014, Kern et al, 2011, and Kern et al, 2013). Activation of the HPA axis has been confirmed both under basal conditions and as the cortisol awakening response ( Kern et al., 2013 ). Moreover, the use of a dynamic test has also proved the existence of HPA axis hyperactivity (Kumpfel et al, 2014 and Ysrraelit et al, 2008). Finally, post-mortem examination of patients with MS revealed that chronic stimulation of the HPA axis results in enlarged adrenals ( Reder et al., 1994 ), increased number of hypothalamic CRH-producing neurons that also co-express AVP ( Huitinga et al., 2004 ) and increased cortisol concentration in cerebrospinal fluid ( Erkut et al., 2002 ).

Therefore, the aim of our study was to evaluate the plasma levels of copeptin and cortisol in newly diagnosed and untreated MS patients. We also intended to verify whether the copeptin levels are related to clinical status, cortisol levels and selected inflammatory parameters.

2. Materials and methods

2.1. Subjects

An MS group consisting of 40 patients (29 women, 11 men) aged between 19 and 57 years with newly diagnosed MS was compared with a control group comprised of 42 individuals (36 women, 6 men) aged between 18 and 51 year with tension type headaches who were determined to not have MS by diagnostic procedures.

The study subjects were consecutive patients who underwent diagnostic procedures for MS and tension type headaches during a one-time hospitalization in a single center (Department of Neurology, Medical University of Warsaw, Bielanski Hospital, Warsaw, Poland) between 2010 and 2013.

According to the medical history, the time from disease onset to confirmation of MS diagnosis varied from one to six months. Based on data obtained from patients (not from medical documentation), remission occurred only in a few subjects, and the number of relapse episodes was between 1 and 3.

At the time of hospitalization when the study enrollment took place, all patients in whom MS was suspected were symptomatic (with disease relapse), and they were naïve to treatment.

The diagnosis of MS was established according to the Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the “McDonald Criteria” ( Polman et al., 2011 ).

Both MS patients and the controls had an MRI brain scan with gadolinium contrast, and cerebrospinal fluid was taken to determine the presence of oligoclonal bands and the CSF IgG index. The neurological deficit was evaluated using the Expanded Disability Status Scale (EDSS). Individuals with cardiac, hepatic or renal failure, neoplasms, psychiatric diseases, acute inflammatory processes, diabetes insipidus or other endocrine diseases were excluded from the study. Both systemic glucocorticoid therapy within three months prior to the study and treatment with drugs that possibly influence copeptin and cortisol levels were also among the exclusion criteria. Pregnancy disqualified women from the examination.

The study program was approved by the Ethical Commission of the Centre of Postgraduate Medical Education in Warsaw. Signed consent was obtained from all participants of the study.

2.2. Analytical methods

Blood samples were taken at 8.00 after overnight fasting into tubes containing EDTA and aprotinin (protease inhibitor); samples were separated by centrifugation at 4 °C. The plasma fraction was stored at − 70 °C prior to copeptin, cortisol and interleukin (IL 6, IL 10 and TNF α) determination. Blood samples were also obtained for analysis of CRP (C-reactive protein) level in serum.

Plasma copeptin levels were measured using a commercial enzymatic immunoassay kit (USCN Life Science Inc., Wuhan, China). The sensitivity of this assay was < 6.1 pg/ml. The intra-assay and inter-assay coefficients were 10% and 12%, respectively.

Cortisol concentration was evaluated in plasma to assess the free cortisol fraction and to avoid any confounding factors including protein levels or estrogen influence. Plasma cortisol levels were determined using a commercial RIA kit from Cisbio Assays (Codolet, France). The sensitivity of the kit was < 6.6 nmol/l. The intra-assay and inter-assay coefficients of variation were 5.3% and 8.1%, respectively.

Concentrations of the IL 6, IL 10 and TNFα were estimated using ELISA commercial kits (Pierce Biotechnology Inc., Rockford, IL, USA). The sensitivities for IL 6, IL 10 and TNF α were < 1 pg/ml, < 3 pg/ml and < 2 pg/ml, respectively. The intra-assay and inter-assay coefficients of variation for IL 6 and IL 10 were 10%, and 10%, respectively and those for TNF α were 5.9%, and 7.1%, respectively.

Serum CRP level was assayed by the immunoturbidimetric latex-enriched method using the COBAS Integra (Roche Diagnostics, Mannheim, Germany). CRP < 5 mg/l was considered to be within the normal range.

2.3. Anthropometric measurements

Anthropometric measurements were performed to determine each subject's weight, height and body mass index (BMI). BMI was calculated according to the following formula: weight divided by height2[kg/m2]. The MS and control groups were divided into lean and overweight/obese subgroups according to their BMI. Individuals with a BMI ≥ 25 kg/m2were categorized as overweight; this group also included obese subjects with a BMI ≥ 30 kg/m2. The BMI of overweight/obese patients with MS did not differ from that of overweight/obese subjects in the control group.

2.4. Statistical analysis

All statistical analyses were performed using Statistica10 (StatSoft Inc., Tulsa, OK, USA). Data are presented as the mean ± standard deviation of the mean (SD). Data were compared between groups using the Mann–Whitney U test.

The significance of correlations between two variables was determined using the Spearman rank correlation coefficient.

All p values of < 0.05 were considered to be statistically significant.

3. Results

The incidence of hypertension and diabetes mellitus type 2 was presented inTable 1, Table 2, Table 3, and Table 4. MS individuals divided into subgroups did not present differences in BMI and age when compared to the appropriate group of controls (Table 1, Table 2, and Table 3).

Table 1 Clinical characteristics of the multiple sclerosis and control groups.

  Multiple sclerosis

n = 40
Control group

n = 42
p
Women/men 29/11 36/6
Hypertension 5 (12.5%) 5 (12%)
Diabetes mellitus type 2 0 1 (2%)
EDSS a 1.56 ± 0.89 0
Age a 34.43 ± 8.5 32.28 ± 8.1 ns
BMI (kg/m2) 24.45 ± 4.8 24.34 ± 4.6 ns
CRP (mg/l) 1.17 ± 1.1 1.29 ± 1.3 ns
TNF α (pg/ml) 4.54 ± 3.1 5.07 ± 4.62 ns
IL 6 (pg/ml) 1.61 ± 0.9 1.82 ± 0.85 ns
IL 10 (pg/ml) 3.04 ± 2.78 2.39 ± 1.5 ns
Copeptin (pg/ml) 282.1 ± 153.5 221.3 ± 76.75 < 0.05
Cortisol (nmol/l) 348.58 ± 158 337.04 ± 265.3 ns

a At diagnosis.

EDSS — the Expanded Disability Status Scale.

BMI — body mass index.

CRP — C-reactive protein.

TNF — tumor necrosis factor.

IL — interleukin.

ns — non-significant.

Table 2 Clinical characteristics of lean subjects with multiple sclerosis and lean controls.

  Multiple sclerosis

BMI < 25

n = 24
Control group

BMI < 25

n = 29
p
Women/men 21/3 25/4
Hypertension 2 (8%) 2 (7%)
Diabetes mellitus type 2 0 0
EDSS a 1.40 ± 0.78 0
Age a 31.92 ± 7.4 30.80 ± 8.0 ns
BMI (kg/m2) 21.40 ± 1.58 22.09 ± 2.1 ns
CRP (mg/l) 1.06 ± 1.18 0.95 ± 0.9 ns
TNF α (pg/ml) 5.18 ± 3.8 6.13 ± 5.3 ns
IL 6 (pg/ml) 1.24 ± 0.7 1.56 ± 0.8 ns
IL 10 (pg/ml) 4.32 ± 3.3 2.24 ± 1.56 < 0.05
Copeptin (pg/ml) 263.62 ± 153.0 221.39 ± 80.3 ns
Cortisol (nmol/l) 316.04 ± 345.0 345.02 ± 309 ns

a At diagnosis.

EDSS — the Expanded Disability Status Scale.

BMI — body mass index.

CRP — C-reactive protein.

TNF — tumor necrosis factor.

IL — interleukin.

ns — non-significant.

Table 3 Clinical characteristics of overweight/obese subjects with multiple sclerosis and overweight/obese controls.

  Multiple sclerosis

BMI ≥ 25

n = 16
Control group

BMI ≥ 25

n = 13
p
Women/men 8/8 11/2
Hypertension 3 (18%) 3 (23%)
Diabetes mellitus type 2 0 1 (8%)
EDSS a 1.81 ± 0.85 0
Age a 38.19 ± 8.8 35.6 ± 7.6 ns
BMI (kg/m2) 29.03 ± 4.3 29.36 ± 4.7 ns
CRP (mg/l) 1.31 ± 0.96 2.07 ± 1.6 ns
TNF α (pg/ml) 3.64 ± 1.6 2.96 ± 1.2 ns
IL 6 (pg/ml) 2.11 ± 0.9 2.34 ± 0.7 ns
IL 10 (pg/ml) 1.76 ± 1.3 2.7 ± 1.5 ns
Copeptin (pg/ml) 309.82 ± 154.9 220.94 ± 71.3 < 0.05
Cortisol (nmol/l) 397.39 ± 92.9 316.01 ± 75.21 < 0.05

a At diagnosis.

EDSS — the Expanded Disability Status Scale.

BMI — body mass index.

CRP — C-reactive protein.

TNF — tumor necrosis factor.

IL — interleukin.

ns — non-significant.

Table 4 Clinical characteristics of subjects with multiple sclerosis divided into lean and overweight/obese subsets.

  Multiple sclerosis

BMI < 25

n = 24
Multiple sclerosis

BMI ≥ 25

n = 16
p
Women/men 21/3 8/8
Hypertension 2 (8%) 3 (18%)
Diabetes mellitus type 2 0 0
EDSS a 1.40 ± 0.78 1.81 ± 0.85 ns
Age a 31.92 ± 7.4 38.19 ± 8.8 < 0.05
BMI (kg/m2) 21.40 ± 1.58 29.03 ± 4.3 < 0.001
CRP (mg/l) 1.06 ± 1.18 1.31 ± 0.96 ns
TNF α (pg/ml) 5.18 ± 3.8 3.64 ± 1.6 ns
IL 6 (pg/ml) 1.24 ± 0.7 2.11 ± 0.9 < 0.01
IL 10 (pg/ml) 4.32 ± 3.3 1.76 ± 1.3 < 0.05
Copeptin (pg/ml) 263.62 ± 153.0 309.82 ± 154.9 ns
Cortisol (nmol/l) 316.04 ± 345.0 397.39 ± 92.9 < 0.05

a At diagnosis.

EDSS — the Expanded Disability Status Scale.

BMI — body mass index.

CRP — C-reactive protein.

TNF — tumor necrosis factor.

IL — interleukin.

ns — non-significant.

Plasma copeptin concentrations in all the patients with MS (overweight/obese and lean) were significantly higher when compared to the controls (p < 0.05; Table 1 ). In the overweight/obese patients with MS plasma, copeptin levels were markedly higher than those of the overweight/obese control subjects (p < 0.05; Table 3 ). The tendency to have a higher plasma copeptin concentration was observed in MS lean patients in comparison with the lean controls, but this difference was not significant ( Table 2 ).

Plasma cortisol levels were markedly higher in MS overweight/obese patients compared with results of the individuals from the appropriate overweight/obese control group (p < 0.05; Table 3 ) and MS lean patients (p < 0.05; Table 4 ).

We did not notice any significant differences in the concentrations of IL 6, IL 10, TNF α and CRP between MS and control individuals when investigated as whole groups ( Table 1 ) or in overweight/obese patients with MS compared to the overweight/obese control subjects ( Table 3 ). However, we observed an increased plasma IL 10 concentration in MS lean individuals when compared to the lean controls (p < 0.05; Table 2 ). Moreover, in MS lean patients, we also noticed a lower IL 6 concentration (p < 0.01) and higher IL 10 levels (p < 0.05) in comparison to overweight/obese patients with MS ( Table 4 ).

In patients with MS, statistically significant positive correlations were found between copeptin and cortisol levels (r = 0.37; p < 0.05), and non-significant correlations were found between copeptin concentration and age (r = 0.29; p = 0.07) and BMI (r = 0.29; p = 0.07). In MS patients, cortisol level positively correlated with CRP level (r = 0.32; p < 0.05) ( Table 5 ). In the control group, significant correlations were found between copeptin and IL 10 concentrations (r = 0.36; p < 0.05), as well as between cortisol and CRP levels (r = 0.31; p < 0.05) ( Table 6 ).

Table 5 Correlations in the multiple sclerosis group.

Parameter A Parameter B R p
Copeptin Age 0.29 = 0.07
Copeptin BMI 0.29 = 0.07
Copeptin Cortisol 0.37 < 0.05
Cortisol CRP 0.32 < 0.05

BMI — body mass index.

CRP — C-reactive protein.

Table 6 Correlations in the control group.

Parameter A Parameter B R p
Copeptin IL 10 0.36 < 0.05
Cortisol CRP 0.31 < 0.05

IL — interleukin.

CRP — C-reactive protein.

4. Discussion

To the best of our knowledge, there are no previous reports concerning copeptin levels in the course of MS. The results of our study revealed that copeptin levels of the entire group of patients with MS were markedly increased when compared to the controls. Because the role of inflammation with an increase of copeptin concentration was confirmed in several diseases, we speculated that the inflammatory process might also connect copeptin and MS. However, we did not find any significant correlation between copeptin and selected markers of inflammation in MS patients or in the controls. Another point that should be discussed is the potential impact of adiposity on the copeptin concentration. In the previously published study, it was found that copeptin level was associated with obesity, including the abdominal form of adiposity ( Enhörning et al., 2011 ). Data from our current research showed the tendency for higher levels of copeptin in overweight/obese subjects with MS in comparison to normal weight MS individuals. However, the differences were found to be non-significant. Moreover, we observed that in the overweight/obese patients with MS the copeptin levels were markedly higher than those of the overweight/obese control subjects. In addition, in MS patients, a positive but non-significant correlation was found between copeptin level and BMI. Those results might suggest the role of connected pathological processes between MS and amount of adipose tissue in secretion of copeptin.

It is widely accepted that glucocorticoids modulate the inflammatory process and control autoimmunity ( Ferreira et al., 2014 ). MS patients are thought to have impaired hypothalamo-pituitary–adrenal axis activity (Kumpfel et al, 2014, Kern et al, 2011, and Kern et al, 2013). However, we found that in newly diagnosed MS individuals, basal plasma cortisol levels did not markedly differ when compared to the controls. However, after dividing the study participants according to BMI into lean and overweight/obese subgroups, we observed higher levels of cortisol in the overweight/obese MS subset compared with the results of their overweight/obese control counterparts as well as with the lean MS group. The explanation of our results must relate to several confounding factors that may influence cortisol concentration.

First, it has been reported that MS patients have increased numbers of CRH-immunoreactive neurons coexpressing vasopressin (CRH/VP neurons) that are believed to be a sign of chronic activation of CRH neurons and increased CRH mRNA expression ( Huitinga et al., 2004 ). Therefore, enhanced copeptin production and secretion stimulate ACTH secretion. In our MS study population, we found a positive correlation between copeptin and cortisol concentrations.

Secondly, a rise in cortisol levels observed in overweight/obese individuals suffering from MS may be linked to the metabolic activity of increased adipose tissue mass. It has been found that 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity that converses inactive cortisone to cortisol is enhanced in subcutaneous adipose tissue in obese men and women. However, the results of the studies concerning the effect of obesity on visceral adipose tissue 11β-HSD1 activity are equivocal because both elevation and no change were reported in the literature ( Chapman et al., 2013 ).

Thirdly, the enhanced cortisol production that was observed in our overweight/obese MS participants may be the result of the rise of pro-inflammatory factor concentrations. It has been suggested that cytokines play a role in the up regulation of 11β-HSD1 and down regulation of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) ( Chapman et al., 2013 ). Regrettably, we failed to find any significant differences in pro-inflammatory IL 6 and TNF α concentrations between MS subjects and the controls including the results of the entire group and when the group was divided according to BMI. However, there were significant differences in concentrations of IL 6 and IL 10 when normal weight and overweight/obese MS individuals where compared. Although there was a significant difference in age between the subpopulations of MS patients, we did not confirm any marked correlation between age as one parameter and selected interleukin level as a second parameter. However, we demonstrated a positive correlation between cortisol and CRP levels in the MS group and the control group.

Thus, the data discussed above confirm the hypothesis that many factors are involved in MS pathogenesis.

5. Conclusions

Taking our findings together with those of previously published papers, it could be suggested that alterations of copeptin and cortisol levels in newly diagnosed, untreated patients with MS may be related not only to the primary disease but also to adiposity. An increase in cortisol levels may also be associated with copeptin secretion.

Conflict of interest statement

None declared.

Acknowledgments

This work was supported by grants 501-1-31-22-13 and 501-1-31-22-14 from the Centre of Postgraduate Medical Education.

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Footnotes

a Department of Endocrinology, Centre of Postgraduate Medical Education, Bielanski Hospital, Ceglowska 80, 01-809 Warsaw, Poland

b Department of Neurology, Medical University of Warsaw, Bielanski Hospital, Ceglowska 80, 01-809 Warsaw, Poland

c Department of Neuroendocrinology, Centre of Postgraduate Medical Education, Marymoncka 99/103, 01-813 Warsaw, Poland

lowast Corresponding author.


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