Laboratory Evaluation for Mitochondrial Dysfunction in Multiple Sclerosis Patients

INTRODUCTION

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative  illness which influences over two million individuals globally and is regarded in several countries to be the main trigger of non-traumatic disabilities in younger adults¹. MS is thought to be autoimmune pathology, but it is not yet entirely clear the causes for the autoimmune attack on myelin. Mitochondrial disorder and related oxidativestrain have a significant position in guiding neurodegeneration, as happens in other chronic neurodegenerative disorders².

       Axons in MS lesions incorporate extra mitochondria and an increase in the number of mtDNA removals within the neuronal cell bodies, suggesting that mitochondria are impaired and dysfunctioning. To sustain conduction, demyelinated axons need to consume extra energy. ³.

Patients with MS have elevated levels of compounds in their cerebrospinal fluid (CSF) and blood derived from the catabolism of ATP (hypoxanthine, xanthine, uric acid, uridine, and creatinine). Such research has

firmly endorsed the theory that energy metabolism is impaired in MS patients ⁴.

Patients with MS display substantial differences in the circulating concentrations of various metabolites, though it's still uncertain if under this pathological condition, uric acid decreases, increases or does not alter ⁵.

       It was also shown that brain lactate is formed by anaerobic neuron glycolysis and astrocytes under normal homeostatic conditions to meet acutely increased energy requirements⁶.Evaluation of the serum specimens of MS sufferersdisplayed increased lactate level in the majority of samples compared with controls.  Sign of elevated glycolysis in MS because of mitochondrial dysfunction was strengthened by a link among the number of inflammatory plaques and lactate concentration⁷. The present study was designed to assess mitochondrial dysfunction in MS patients. by investigating lactate and uric acid serum levels.

Subjects AND MATERIALS

At Al-Azhar University Hospitals, Cairo, Egypt, this case control study was conducted. The local Ethics Committee accepted the examineprocedure and the knowledgeable consent of all participants were approved. The research included 32 patients with MS and 20 safe controls matched by age and sex. Patients have been diagnosed with MS as per McDonald's Revised Criteria⁸.Patients were excluded from the study if they had associated conditions affecting serum lactate (body-building exercises, muscle diseases, renal dysfunction, epilepsy, hepatic failure, uncontrolled diabetes mellitus, malignancy or mitochondriotoxicdrugs or substances e.g.: alcohol, cocaine, linezolid, metformin, acetaminophen, beta 2 agonists and theophylline) or uric acid (hypothyroidism, hyperthyroidism, Wilson's disease, obesity, psoriasis or use of diuretic medications or uricosurics) levels.

Careful history taking, thorough general and neurological examination and laboratory investigation (CBC, ALT, AST, albumin, urea, creatinine, RBS, serum lactate and uric acid) were carried out by all participants. The degree of disability in sufferers with MS became evaluated the usage of the expanded disability status scale (EDSS) [9] and fatigue becameassessed using the fatigue severity scale  (FSS) ⁹.

Data obtained from the present study were statistically analyzed using SPSS 22 (IBM, USA). Compared to the t test, numerical data were expressed as mean ± standard deviation and the number and percentage of categorical data were represented and compared with the exact Fisher test. Using Pearson's correlation coefficient, correlation became achieved among numerical values.

RESULTS

The present case control study involved 32 patients with MS and 20 controls matched by age and sex (Table1). The studied patients comprised 27 patients (84.4 %) with relapsing-remitting MS (RRMS) and 5 patients (15.6 %) with secondary progressive MS (SPMS) (Table 2).Patients received significantly higher serum lactate levels relative to controls (40.7± 18.1 versus 20. 1 ± 5.8 mg/dl, p=0.001). There were no statistically relevant variations among patients and controls regarding serum uric acid levels (4.9± 1.1 versus 5.3 ± 1.2 mg/dl, p=0.337) (Table1). No substantial variations were noted among RRMS and SPMS patients regarding serum lactate and uric acid levels. Correlation analysis showed significantly inverse correlation between serum lactate levels and both EDSS (r=-0.421, p=0.016) and FSS (r=-0.504, p=0.003) (Table3).

Table 1: Demographic and laboratory data in patients and controls.

EDSS: Expanded Disability Status Scale, FSS: Fatigue Severity Scale 

Table 2: Clinical data in the studied patients

Table 3: Correlation between lactate and uric acid levels and the clinical data

DISCUSSION

The current research showed elevated serum lactate levels in patients with MS as relativeto 20 normal healthy controls. Thisresult can confirm the theory that mitochondrial impairment plays a significant position in MS pathogenesis and is particularly relevant to the disease's neurodegenerative phase. Our results are supported byHassan and Mehaney ¹⁰. In their work, MS patients had substantially higher lactate serum levels alongside lower UA serum levels as compared to healthy controls.Our findings are also supported by the Amorini, Nociti ⁷who reported thatserum lactate levels in MS patients were three

times higher than in healthy controls. Interestingly, the study ofAlbanese, Zagaglia ⁶showed that lactate was better in patients' cerebrospinal fluid than in controls.

In comparison, our present study demonstrated no statistically substantial variations amongserum UA levels in MS patients as compared to healthful controls. These findingssupported by the study ofGosch, Davis ¹¹in which 499 MS patients were relative to 276 healthy controls. Similar conclusions were reported byKohansal, Farahani ¹².Of note,Massa, O’reilly ¹³prospective study found a tendency towards a reduced risk of MSbetween people with higher serum uric acid;however  the association become now no longer significant. In another work, Uric acid serum levelshave beenassessed in sixtysufferers with MS without relapse throughout the lastthree monthsand thirty healthy controls with no significant differences among groups¹⁴.

In contrast to our study,Ashtari, Bahar ¹⁵on 130RRMS patients and 50 controlsobserved substantially decreaselevels of uric acid in MS sufferers with relapsing disease in comparison to those with remitting disease and controls. Moreover,Liu, Shen ¹⁶discovered thatserum UA levels had decrease in MS sufferers relative to healthful controls and different neurological inflammatory diseases.

On the other hand,an increase in circulating uric acid and other oxypurines(xanthine and hypoxanthine) as well as β-pseudouridine and uridine was observed for patients with MS in another study that included 170 MS patients and 163 healthy controls.Concomitant rises in circulating creatinine, malondialdehyde, nitrite and nitrate and reductions in ascorbic acid suggest that MS causes changes in the metabolism of energy and balance of oxidants / antioxidants which may be controlled within the serum of patients with MS¹⁷.

CONCLUSION

According to our study and in the previous studies, lactate levels are elevated in both serum and CSF in patients with MS, but its role as a potential biomarker for the disease progression and activity is still controversial and 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.