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April2015 Vol.52 Issue:      2 Table of Contents
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Serum Lactate and Uric Acid as Biomarkers for Disease Activity and Progression in Multiple Sclerosis

Amr Hassan1, Dina Mehaney2

Departments of Neurology1, Chemical Pathology2; Cairo University; Egypt



ABSTRACT

 

Background: Multiple sclerosis (MS) is a primary inflammatory demyelinating disease that could be associated with a secondary progressive neurodegenerative component. Objective: To investigate the serum levels of lactate and uric acid (UA) in MS patients and to explore their potential role as biological markers for monitoring the disease activity and progression. Methods: This case-control study was conducted on 89 Egyptian subjects (55 multiple sclerosis patients=Group I) and 34 normal healthy individuals (Control group = Group II). Group I patients were subjected to thorough history taking, detailed neurological examination and clinical assessment of the severity of the disease using Expanded Disability Status Scale (EDSS). Serum level of lactate and uric acid were measured in both groups. Results: In comparison to the control group, subjects with multiple sclerosis had statistically significant higher serum level of lactate (P=0.005), along with lower serum levels of UA (P=0.001), however, there was no statistically significant correlation between their levels and duration of illness, EDSS scores or number of attacks. Conclusion: MS patients have significantly higher serum lactate level. This can support the hypothesis that mitochondrial dysfunction has an important role in the underlying pathogenic mechanism of the disease. MS patients have also significantly lower uric acid level than normal control; reflecting its important role as an antioxidant in the prevention of disease activity. However, their potential value as markers for monitoring disease activity and progression is questionable. [Egypt J Neurol Psychiat Neurosurg.  2015; 52(2): 127-131]

 

Key Words: Multiple Sclerosis, Serum Lactate, Uric Acid.

Correspondence to Amr Hassan El Sayed Mohammed. Neurology Department - Cairo University, Egypt.

Tel.: +201006060809 Email:  amrhasanneuro@kasralainy.edu.eg

 





Introduction

 

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system affecting white and possibly grey matter. MS is characterized by multiple focal demyelinating lesions affecting the white matter, which is not infrequently associated with cortical demyelination and which may be preceded by destruction of oligodendrocytes and apoptosis1,2. Mitochondrial DNA alterations, abnormal mitochondrial enzyme activities, mitochondrial DNA repair defects and increased production of free radicals have been reported to increase in MS patients and animal models3. Impaired mitochondrial can promote neurodegeneration and cause increased anaerobic metabolism in MS4. Measurement of serum lactate in MS patients might be relatively an inexpensive test for monitoring of the assumed hypoxia in MS4. There is an increasing number of reports on anti-oxidant substances such as uric acid (UA) in MS, in order to identify reliable disease activity and disability progression markers5-8. Several studies had showed decreased UA levels serum

 

in MS patients, and possible relationships between level of UA and disease outcomes, with lower levels of UA in patients presenting with higher disease activity, higher relapse rate and disability scores [5,9-11]. The aim of our study was to determine whether MS patients had values of circulating lactate and uric acid different from those of controls and their potential role as biomarkers for monitoring disease activity and progression.

 

Subjects and Method

 

Subjects

This case-control study was conducted on 89 Egyptian subjects (55 multiple sclerosis patients (patients group = group I) and 34 normal healthy control (control group = group II) 

 

Inclusion criteria:

We included patients with multiple sclerosis (RRMS and SPMS) (according to the revised McDonald's criteria) 12 from both sexes whose age ranged 10-50 years.

 

 

Exclusion criteria:

We had excluded patients with any other medical conditions that may affect the serum lactate level (such as diabetes mellitus, severe iron-deficiency anemia, liver disease, alcoholic ketoacidosis, pancreatitis, malignancy, infection, renal failure and seizures) or the serum UA level (such as gout and hypertensive patients on diuretics).

Patients in the study group were recruited from the Multiple Sclerosis Unit, Kasr Al-Aini Hospitals, and Cairo University over the period from October 2014 until January 2015.

 

Methods

All patients in group (I) were subjected to:

1.                Clinical assessment:

Full history taking, general medical examination and thorough neurological examination according to the modified multiple sclerosis sheet officially used in MS unit, Neurology Department, Cairo University.

2.                Expanded disability status scale (EDSS)13:

The degree of disability for all patients was rated according to the EDSS, that provides overall rating of disabilities based on a (0) (normal neurological examination) to (10) death due to MS.

 

All participants in both groups were subjected to:

1.            Measurement of serum lactate and uric acid:

a.    Collection of serum and plasma samples:

5 ml of blood was collected and divided into two tubes: one containing sodium fluoride-potassium oxalate for plasma separation and the other one was a plain tube, in which the sample was allowed to clot for serum separation.

b.   Biochemical testing:

Plasma lactate was assayed according to Trinder method14. All assays were carried out with Bechman Coulter AU480 autoanalyzer (USA). Serum uric acid was determined according to the modified Trinder method described by Fossati et al.15,16.

2.            Statistical analysis:

Data were statistically described in terms of mean ± standard deviation (± SD) and compared using Student t test for independent samples. Correlation between various variables was done using Pearson moment correlation equation for linear relation in normally distributed variables and Spearman rank correlation equation for non-normal variables/non-linear monotonic relation. p values less than 0.05 was considered statistically significant. All statistical calculations were done using computer program SPSS (Statistical Package for the Social Science; SPSS Inc., Chicago, IL, USA) release 15 for Microsoft Windows (2006).

 

ResultS

 

Characteristics of the study population:

This study included 55 patients with MS and 34 age and sex-matched healthy controls. The mean age of the patients group was 33.37 ±9.13 while it was  32.6 ±8.31 years in the control group. In the patients group, the frequency of females and males was 61.8% (n= 34) and 38.2% (n= 21) respectively, while in the control group, there were 21 females (61.8%) and 13 males (38.2%). The mean duration of the disease in patients was 6.1±5.07 years. The mean duration since the last attack was 16.41±18.1 months. The mean of the total number of the attacks was 4.07±2.7. The mean number of attacks over the past two years was 1.45±1.2.  The mean EDSS score was 3.83±2.01. The most frequent MS type was relapsing remitting MS (46 patients =83.6%), followed by the secondary progressive MS (8 patients =14.5%) and lastly the primary progressive MS in only one patient (1.9%).

 

Results of the serum lactate and uric acid:

As shown in Table (1), The mean serum lactate level in the patients group was 15.88±6.42  mg/ dl, while in the control group, it was 12.09(4.08). This difference was highly statistically significant (p=0.005). Table (2) Shows that serum uric acid level in the patients group was lower than that in the control group as the mean serum UA was 4.35±1.36 and 5.62±1.87 respectively. This difference was also highly statistically significant (p=0.001).

 

Correlation between serum levels of lactate, uric acid and clinical variables:

Table ​ (3) presents the correlations between serum levels of lactate and uric acid in the patients group and the clinical variants like age of patients, the duration of the illness, the duration since the last attack, the number of attacks and the EDSS score. There was no significant correlation between the levels of serum lactate, uric acid and different clinical parameters apart from the statistically significant positive correlation between age and serum level of uric acid (r=0.306, p=0.029).

 

 


Table 1. Serum lactate levels in MS patients and controls.

 

 

Patients group

(n=55)

Control group

(n=34)

P-value

Minimum (mg/dl)

5.3

6.5

 

Maximum (mg/dl)

36

21

 

Mean ±SD (mg/dl)

15.88(6.42)

12.09(4.08)

0.005*

*Significant at P<0.01

 

Table 2. Serum uric acid levels in MS patients and controls.

 

 

Patients group

(n=55)

Control group

(n=34)

P-value

Minimum(mg/dl)

2

2.9

 

Maximum(mg/dl)

9.6

9.6

 

Mean ±SD (mg/dl)

4.35(1.36)

5.62(1.87)

0.001**

*Significant at P<0.01

 

Table 3. Correlation between serum lactate, uric acid and clinical variables.

 

 

Serum  lactate level

Mean (SD)

Mg/dl

Serum  uric acid level

Mean (SD)

Mg/dl

Age

r

0.047

0.306

P. value

0.764

0.029*

Duration of illness

r

-0.161

-0.036

P. value

0.307

0.807

Duration since the last attack

r

0.177

-0.067

P. value

0.256

0.640

Number of attacks

r

-0.093

-0.246

P. value

0.554

0.082

EDSS score

r

-0.194

0.181

P. value

0.213

0.203

*Significant at P<0.05

 

 


Discussion

 

The present study demonstrated the increased serum levels of lactate in the Egyptian MS patients as compared to controls. This finding may support the hypothesis that mitochondrial dysfunction has a crucial role in the pathogenesis of MS and of its particular relevance to the neurodegenerative component of the illness.

These findings are supported by the results of a recent multicenter study that has been published in 2014 in which 613 MS patients were recruited, assessed for the clinical disability and serum lactate level.  They found that levels of serum lactate in patients with MS was three times higher than that of healthy controls group along with higher levels in cases with a progressive than with a relapsing-remitting disease course. However, in contrast to our results, that did not find a significant correlation between lactate and clinical disability, they found a linear correlation between serum lactate levels and the expanded disability scale (EDSS) 4. There is paucity of reports as regard the role of lactate as a potential biomarker for the disease progression and activity; therefore, further studies should be encouraged for better exploration of the importance of lactate serum levels and of its variations in relation to the course of the disease and disability progression.

The present study demonstrated also statistically significant reduced serum levels of UA in the Egyptian MS patients as compared to healthy controls. This finding suggests the reduction of antioxidant reserves during the course of MS. Our results are supported by Fereshteh et al., who found a significant difference between mean UA concentration in patients with relapsing MS and controls (p = 0.002)17. Moreover, In 2012, a multicenter study The serum UA levels were lower in patients with MS than in healthy controls Similarly, the serum UA levels decreased in MS patients with clinical activity when compared to MS with clinical inactivity patients with relapse in comparison to RRMS patients with remission10. This finding is also matching with many other studies that reported the significantly lower serum level of UA in MS patients9-11.

Our results did not find a significant correlation between the serum uric acid levels and the disease duration, number of the attacks and EDDS scores.

These negative results are supported by the results of Liu et al who  suggested that serum UA levels did not correlate with higher (or lower) expanded disability status scale and magnetic resonance imaging (MRI) activity10. However, in contrast to our data, a cross-sectional study, found an inverse relationship between UA levels and disease duration18.

Our study suggests that both serum lactate and UA are relevant to MS. Their potential use as biomarkers for monitoring disease activity and progression is doubtful.

 

[Disclosure: Authors report no conflict of interest]

 

references

 

1.        Frohman EM, Racke MK, Raine CS. Multiple sclerosis. The plaque and its pathogenesis. N Engl J Med. 2006; 354:942–955.

2.        Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann Neurol. 2000;47: 707–17.

3.        Mao P1, Reddy PH. “Is Multiple Sclerosis a Mitochondrial Disease?” Biochim Biophys Acta. 2010 Jan;1802(1):66-79.

4.        Amorini AM, Nociti V, Petzold A, Gasperini C, Quartuccio E, Lazzarino G. et al. Serum lactate as a novel potential biomarker in multiple sclerosis. Biochim Biophys Acta. 2014 Jul;1842(7):1137-43.

5.        Hooper DC, Bagasra O, Marini JC, Zborek A, Ohnishi ST, Kean R, et al. Prevention of experimental allergic encephalomyelitis by targeting nitric oxide and peroxynitrite: implications for the treatment of multiple sclerosis. Proc Natl Acad Sci USA. 1997; 94(6):2528–33.

6.        Hooper DC, Scott GS, Zborek A, Mikheeva T, Kean RB, Koprowski H, et al. Uric acid A peroxynitrite scavenger inhibits CNS inflammation blood– CNS barrier permeability changes and tissue damage in mouse model of multiple sclerosis. FASEB J. 2000;14(5):691–8.

7.        Squadrito GL, Cueto R, Splenser AE, Valavanidis A, Zhang H, Uppu RM, et al. Reaction of uric acid with peroxinitrite and implications for the mechanism of neuroprotection by uric acid. Arch Biochem Biophys. 2000; 376(6):333–7.

8.        Scott GS, Spitsin SV, Kean RB, Mikheeva T, Koprowski H, Hooper DC. Therapeutic intervention in experimental allergic encephalomyelitis by administration of uric acid precursors. Proc Natl Acad Sci USA. 2002; 99(25):16303–8.

9.        Ashtari F, Bahar M, Aghaei M, Zahed A. Serum uric acid level in patients with relapsing-remitting multiple sclerosis. J Clin Neurosci 2013;20(5):676-8.

10.     Liu B, Shen Y, Xiao K, Tang Y, Cen L, Wei J. Serum uric acid levels in patients with multiple sclerosis: a meta-analysis. Neurol Res. 2012;  34(2):163–71.

11.     Dujmovic I, Pekmezovic T, Obrenovic R, Nikolić A, Spasic M, Mostarica Stojkovic M, et al. Cerebrospinal fluid and serum uric acid levels in patients with multiple sclerosis. Clin Chem Lab Med. 2009;47:848-53.

12.     Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M,et al. Diagnostic criteria for multiple sclerosis 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69:292.

13.     Kurtzke J. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology.1983; 33: 1444-52.

14.     Trinder P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 1969;6:24-27.

15.     Fossati, P, Prencipe, L, Berti, G., Clin Chem. 1980;26: 227.

16.     Tietz, N.W. Clinical Guide to Laboratory Tests, 4th Edition. W.B. Saunders; 2006.

17.     Fereshteh A, Mohammadali B, Maryam A, Arash Z. Serum uric acid level in patients with relapsing-remitting multiple sclerosis. J Clin Neurosci. 2013; 20(5):676 – 8.

18.      Moccia M, Lanzillo R, Palladino R, Russo C, Carotenuto A, Massarelli M, et al. Uric acid: a potential biomarker of multiple sclerosis and of its disability. Clin Chem Lab Med. 2015 Apr 1;53(5):753-9.


 

 

 

 

 

 

 

 

 

الملخص العربي

 

اللبنات وحامض البوليك بالدم كمؤشرين حيويين لنشاط وتقدم مرض التصلب المتعدد

 

يعد مرض التصلب المتعدد من الأمراض التي شاعت مؤخرا وهو ينشأ نتيجة خلل بالجهاز المناعي يؤدي إلي التهاب الغلاف الدهني لأعصاب الجهاز العصبي المركزي.ولمرض التصلب المتعدد أعراض كثيرة مثل: اختلال الجهاز الحركي أو الجهاز الحسي. يهدف هذا البحث إلى دراسة مستوي اللبنات وحامض البوليك بالدم كمؤشرين حيويين لنشاط وتقدم مرض التصلب المتعدد وماذا إذا كان يختلف عن مستوياتهما في الأصحاء.

أُجريت الدراسة على 55 مريضا مصريا مصابين بالتصلب المتعدد حسب مواصفات ماكدونالد للتصلب المتعدد لعام 2010. وقد تم اختيار العينة من وحدة التصلب المتعدد – مستشفي قصر العيني – جامعه القاهرة طبقا للمواصفات التالية:

1-              العمر يتراوح من 10-50 سنه من كلا الجنسين.

2-              تم استبعاد المرضى الذين يعانون من أي مرض آخر يؤثر على مستوي اللبنات وحامض البوليك بالدم

وتم اختيار 34 متطوعا من الأصحاء كمجموعه ضابطه.

 

وقد خضع المرضى للفحوص والاختبارات التالية:

1-              فحص إكلينيكي وعصبي.

2-              مقياس كيرتزك لقياس الإعاقة الجسدية.

وخضع جميع المشاركين بالخث من المرضي والأصحاء لدراسة معمليه لمستوي اللبنات وحامض البوليك بالدم.      

 

وكانت نتائج البحث كما يلي:

1-      وجود زيادة ذات دلاله احصائيه عالية في مستوي اللبنات بالدم في مجموعه الدراسة مقارنه بالمجموعة الضابطة

2-      وجود نقص ذو دلاله احصائيه في مستوي حامض البوليك بالدم في مجموعه الدراسة مقارنه بالمجموعة الضابطة

3-      عدم وجود علاقة طرديه ذات دلاله احصائيه بين مستوي اللبنات بالدم ومدة المرض، عدد الانتكاسات، الفترة منذ أخر انتكاسه، درجه الاعاقه حسب مقياس كيرتزك لقياس الإعاقة الجسدية.

4-      عدم وجود علاقة عكسية ذات دلاله احصائيه بين مستوي حامض البوليك بالدم ومدة المرض، عدد الانتكاسات، الفترة منذ أخر انتكاسه، درجه الاعاقه حسب مقياس كيرتزك لقياس الإعاقة الجسدية.

 

ويستنتج من هذا أن مستوي اللبنات وحامض البوليك بالدم مرتبط بمرض التصلب المتعدد ولكن استخدامهما كمؤشرين حيويين للاستدلال على مدي تقدم المرض ودرجه شده الاعاقه يحتاج إلى المزيد من البحث.

 



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