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 Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 2  |  Page : 74-79

Importance of ferritin in sera and cerebrospinal fluid as both a predictive and an etiodiagnostic biomarker in ischemic stroke: a single-center prospective study


1 Department of Clinical Pathology, Pharos University in Alexandria, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Neurology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
3 Critical Care Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt

Date of Submission11-Nov-2015
Date of Acceptance08-Mar-2016
Date of Web Publication6-Sep-2016

Correspondence Address:
Hala Demerdash
Clinical Pathology, Clinical Pathology Department Alexandria University Hospitals, Faculty of Pharmacy Pharos University in Alexandria, 75 Ismail Serry street, Smouha 21311 Alexandria
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2356-9115.189790

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  Abstract 


Background and aim Trace metals such as iron and its storage protein ferritin are known to play an important role in stroke and other neurologic disorders. This prospective study was designed to determine whether cerebrospinal fluid (CSF) ferritin levels aid in evaluation of stroke severity and its prognosis.
Patients and methods Thirty-two patients with a diagnosis of acute stroke due to intrinsic or atherosclerotic vessel pathology were included in the study within 24 h from onset of symptoms. Immediately after admission, the clinical condition of the patient was evaluated using the Canadian Stroke Scale and was determined periodically during follow-up. Serum and CSF ferritin levels were assayed and correlated with the known biomarker amyloid β protein 1-42.
Results Serum ferritin level revealed significantly greater values in patients with larger-sized lesions (P<0.01) and deteriorated neurologic condition during clinical follow-up. CSF and serum ferritin levels were correlated with neurologic deficit (r=0.50, P<0.001). There was no significant correlation between amyloid β protein 1-42 and ferritin levels (r=0.07, P=0.7). Serum ferritin level and large-sized lesions were independently associated with stroke due to Intracranial atherosclerotic disease pathology. Increased serum ferritin levels correlated with severity of stroke and the size of the lesion.
Conclusion Our results revealed that elevated values of CSF and serum ferritin may indicate a poor prognosis in terms of neurologic deterioration in intracranial atherosclerotic (ICAD)-induced stroke patients.

Keywords: Canadian Stroke Scale, cerebrospinal fluid ferritin, intracranial atherosclerosis, serum ferritin, stroke


How to cite this article:
Demerdash H, Mansour O, Zytoun T, Megahed M. Importance of ferritin in sera and cerebrospinal fluid as both a predictive and an etiodiagnostic biomarker in ischemic stroke: a single-center prospective study. Res Opin Anesth Intensive Care 2016;3:74-9

How to cite this URL:
Demerdash H, Mansour O, Zytoun T, Megahed M. Importance of ferritin in sera and cerebrospinal fluid as both a predictive and an etiodiagnostic biomarker in ischemic stroke: a single-center prospective study. Res Opin Anesth Intensive Care [serial online] 2016 [cited 2020 Jun 4];3:74-9. Available from: http://www.roaic.eg.net/text.asp?2016/3/2/74/189790




  Introduction Top


Ferritin is a major cellular iron storage protein. It is the known source of iron for the synthesis of iron-containing proteins such as cytochromes. In brain tissue, ferritin is localized in astrocytes and microglia [1]. Serum concentration of ferritin is known to be directly proportional to iron stores in tissues and therefore may be used to evaluate iron stores in the absence of inflammatory conditions, infectious diseases, and cancer [2]. Low serum ferritin level indicates decreased iron stores.

Atherosclerosis is a multifactorial disease characterized by endothelial dysfunction, smooth muscle cell proliferation, inflammation, lipid accumulation, and thrombus formation. Classical risk factors for atherosclerosis generally include hypertension in men, diabetes, advanced age, smoking, and hypercholesterolemia [3]. In cerebrovascular diseases, oxidative stress and production of oxygen-free radicals are associated with increased amount of iron in the cytosol as a result of release of iron from ferritin [4],[5]. Thus, the ferrous iron-mediated free radical pathway is considered an important factor in the occurrence of acute stroke [6].

Iron can play a role in the initiation and propagation of lipid peroxidation, resulting in altered membrane fluidity, inactivation of membrane-bound enzyme complexes, and eventually disruption of cell membrane and cell death. Therefore, lipid peroxidation is considered to be related to the concentration of tissue iron [6],[7]. Recent studies declared that pathological and biochemical changes start many years before the occurrence of cerebral atherosclerosis and before development of symptoms. Thus, detection of biological markers that aid in the identification of affected individuals in early stages is the most promising way toward a predictive diagnosis [8]. Well-known biomarkers in cerebrospinal fluid (CSF) include amyloid β protein (Aβ)1-42, total τ, and phosphorylated τ. These biomarkers have gained increasing importance in supporting the clinical diagnosis [9]. However, no single marker gives an accurate diagnosis and hence several combinations of CSF biomarkers (Aβ1-42, Aβ1-40, total τ, phosphorylated τ) have been used [10]. Moreover, particular changes in these biomarkers are also detectable in other neurodegenerative and neurologic diseases [9]. Therefore, there is increased need for additional and more sensitive CSF and serum biomarkers for early and differential diagnosis of cerebral atherosclerosis.

Recently, altered metal homeostasis was thought to be an important factor in the pathogenesis of atherosclerosis due to stimulation of the formation of reactive oxygen species and Aβ, which is the major constituent of senile plaque, produced and secreted by human cells as a result of normal cleavage of the amyloid precursor protein [11],[12].

In this study, we tried to find out whether determination of serum and CSF ferritin levels at admission might help in estimating the clinical severity and prognosis of stroke in the early period, in addition to other clinical and laboratory parameters.


  Patients and methods Top


This study included 51 patients with acute ischemic stroke who were admitted to the Department of Neurology of Alexandria University Hospital between March 2013 and March 2014. All patients were initially seen within the first 24 h after stroke, enrolled in the study after having an informed written consent from every patients or their relatives’ and approval of the ethical committee ‘‘University of Alexandria Ethical Committee’’. The mean time from the initiation of symptoms to arrival at the hospital was 6.6±4.5 h (range: 2.4–10.8 h). On admission, demographic characteristics, detailed history, and clinical data for risk factors of stroke were documented. The following laboratory tests were performed immediately after admission, except for lipid profile after 12 h fasting: complete blood picture, serum electrolytes, urine analysis, and other biochemical studies including lipid profiles. In addition, all patients were subjected to chest radiography and 12-lead electrocardiography. They were also investigated to elucidate the risk factors for stroke. Computed tomography/computed tomography angiography or MRI/magnetic resonance angiography was performed within the first 24 h after admission and repeated when required during follow-up of the clinical course. Exclusion criteria included incidence of transient ischemic attacks, intraventricular or subarachnoidal hemorrhage, body temperature above 37.5°C, and presence of inflammatory conditions, tumors, or hepatic disease.

Serum and CSF ferritin levels were measured using the ADVIA Centaur Ferritin assay (Siemens, United Kingdom), which is a two-site sandwich immunoassay using direct chemiluminometric technology [13].

CSF Aβ1-42 levels were measured to determine their ability to exhibit oxidative stress and study its relationship with ferritin, using a commercial sandwich ELISA kit (Innogenetics, Ghent, Belgium), specifically constructed to measure β-amyloid containing both the first and 42nd amino acids, with reported high sensitivities and specificities ranging from 80 to 93% [14].

Iron in CSF is determined by direct iron assays developed by using the chromophore (Ferene’: Diagnostic Chemicals Limited.; Charlottetown, Prince Edward Island, Canada) company name.; Charlottetown, Prince Edward Island, Canada) [15].

The nature of stroke was determined as either ischemic in the presence of positive angiographic pathology or non-ischemic under negative angiographic pathology by cranial computed tomography/computed tomography angiography or MRI/magnetic resonance angiography scanning.

According to the arterial system, stroke was classified as either carotid system or vertebrobasilar. Ischemic lesions were then classified according to size into three groups: the first group included small lesions (no lesion or one lesion with a diameter of about 5 mm visible in not more than two adjacent slices); the second group had medium-sized lesions; and the third group had large lesions (involving at least one complete vascular territory) [16].

The outcome of patients was defined as survived or dead. Stroke severity at admission was determined using the Canadian Stroke Scale (CSS) [17]. Functional outcomes of patients were measured with CSS on day 21. Assuming that a neurologic score of 7.5 or above indicated a condition of potential self-sufficiency [17],[18], the patients were classified as follows.

Improved

A final CSS score of 7.5 or above, and higher than the one at admission.

Deteriorated or without relevant improvement

No difference between the initial and follow-up score, or did not exceed a score of 7.

Statistical analyses

All data were analyzed with SPSS® software (Statistical package for social science for personal computers) and presented as mean±SD. The Student t-test, one-way analysis of variance, or the Mann–Whitney test were used for continuous variables and the χ2-test was used for noncontinuous variables. Spearman’s and Pearson’s correlation tests were used to reveal any correlations. Level of significance was chosen as P less than 0.05. Logistic regression analyses were used to evaluate the influence of various independent variables on the outcome as regards survival and neurologic deterioration.


  Results Top


This study was conducted on 51 patients, 30 women and 21 men, aged 36–77 years, with a mean age of 61.8±10.3 years in the Intracranial atherosclerotic disease (ICAD) group and 56.1±11.3 years in the non-ICAD group, who were admitted to the Department of Neurology in Alexandria University Hospital. Thirty-two patients had ischemic stroke due to ICAD and 19 patients had ischemic stroke in the absence of any intrinsic vessel pathology.

The carotid vascular area was involved in 75% of the patients. According to the level of consciousness, patients were ranked as being alert (23 patients), somnolent (14 patients), being in stupor (eight patients), or comatose (six patients). The CSS score was evaluated at the time of admission. The mean CSS score was 4.8±0.4 for the ICAD group and 5.1±2.6 for the non-ICAD group [Table 1].
Table 1 Baseline clinical characteristics and results of laboratory investigations for the internal carotid artery dissection group (group I) and non-internal carotid artery dissection group (group II)

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Significantly higher serum ferritin levels were seen in the ICAD group of patients with cerebral stroke compared with that in the non-ICAD group. In addition, ferritin concentration in CSF was significantly higher in the ICAD group than in the non-ICAD group [Table 2].
Table 2 Measured biomarker in both serum and cerebrospinal fluid in both groups

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Further, there was a significant negative correlation between the mean serum ferritin concentration and initial CSS score (r=−0.421, P<0.01) in group I. Accordingly the serum ferritin level was significantly higher in patients with marked neurologic deficit, as evident by the initial CSS score. Serum ferritin level was significantly different among patients according to the level of consciousness in group II (r=−0.165, P≤0.05) [Table 3].
Table 3 Correlation between serum ferritin and cerebrospinal fluid ferritin and amyloid β protein 1-42 and cerebrospinal fluid iron in both groups

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Patients with neurological deterioration had higher mean serum ferritin level compared with those whose condition improved (P<0.01). Also, large lesion size was associated with significantly higher mean serum ferritin level (388.74±50.92 ng/ml) compared with medium lesion size (219.0±32.89 ng/ml) and small-sized lesion (147.57±21.18 ng/ml) (P<0.01).

The results of CSF Aβ1-42 demonstrated a significantly lower level in the ICAD group compared with the non-ICAD group [Table 2].

However, there was no significant correlation between CSF Aβ1-42 levels and other variables, including CSF and serum ferritin level, in both groups [Table 3]. Moreover, both total cholesterol and LDL-cholesterol revealed no significant correlation with serum ferritin level in both studied groups (P>0.05) [Table 4].
Table 4 Correlation between serum ferritin and serum cholesterol/LDL-cholesterol in both groups

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In univariate analysis, serum ferritin and CSF ferritin levels, CSS score at admission, and larger size of lesion were significantly higher in the ICAD group but not age, sex of the patients, CSF Aβ1-42 level, or nature or laterality of the lesion.

A stepwise multivariate logistic regression analysis was then performed including serum and CSF ferritin levels, age, CSF Aβ1-42 level, CSF iron level, serum total cholesterol and LDL-cholesterol, initial CSS score, and size of the lesion. Variables significantly predictive of deterioration are shown in [Table 5]; the most effective variable was CSF ferritin level [P=0.001, odds ratio (OR)=2.11], followed by serum ferritin level (P=0.005, OR=2.98). Moreover increased iron concentration in CSF was independently and significantly associated with cerebral stroke due to ICAD (P=0.012, OR=1.41). Other less significant variables included total cholesterol and LDL-cholesterol.
Table 5 Multivariate analysis of different risk factors identified to predict deterioration

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  Discussion Top


There have been few clinical studies investigating the role of CSF and serum ferritin levels in cerebrovascular diseases, as scientists who discussed these biomarkers studied them under different stroke etiologies.

Some studies stated that ferritin concentration in CSF might be a major factor in the severity of inflammatory reaction as it might play a role in tissue damage and it was found to be higher than normal in various diseases in which the blood–brain barrier was impaired [19],[20],[21].

In the current study we found a significant link between ICAD-associated stroke and CSF ferritin level when compared with non-ICAD stroke. This may be explained from the hypothesis that ICAD primes brain cells through intrinsic biochemical cascades to aggravate the cytotoxic stress when compared with non-ICAD pathology. In contrast, Milman et al. [22] revealed that ferritin level in CSF had no practical value in the diagnosis of patients with meningeal reaction and cerebrovascular events. Also other studies predicted a relationship between high serum ferritin level and poor prognosis in ischemic stroke [23],[24].

Dávalos et al. [23] demonstrated a correlation between serum ferritin level determined on the first day after acute ischemic stroke and degree of deterioration of the patient’s condition on day 30 of follow-up. Moreover, in another study, the relation between serum ferritin and prognosis of stroke was found to be independent of the infarct volume [25].

The results of the present study revealed significantly elevated ferritin levels in patients with large-sized lesion, severe degrees of neurologic deficit, and attenuated levels of consciousness at the time of admission, according to CSS, which was associated with poor prognosis in terms of neurologic deterioration and ICAD pathology in stroke patients. In univariate analysis, serum ferritin levels, initial CSS scores denoting the severity of the patient’s condition, CSF Aβ1-42 levels, and large size of lesion results were significantly different. The same variables might be valuable in determining the prognosis of the patient’s clinical status, except CSF Aβ1-42 level. In multivariate analysis, serum ferritin level and large size of lesion were significantly important factors determining mortality as a dependent variable. Initial CSS score and serum ferritin level were found to be independent predictors of neurologic deterioration.

Our results are consistent with those of previous studies that evaluated the relationship between serum ferritin level, clinical features, and prognosis [23],[24]. Although only ischemic stroke was taken into account in some of the previous studies, both ICAD ischemic stroke and non-ICAD ischemic stroke were included in our study. In previous studies, the relationship between initial serum ferritin level and clinical severity of the patient’s condition was not determined.

In this study, we found no correlation between serum ferritin and cholesterol, both total cholesterol and LDL-cholesterol, in ICAD and non-ICAD groups. However, both total cholesterol and LDL-cholesterol were found to be less predictive in the prognosis of patients with ICAD, despite the fact that cholesterol is known to have an effect in blood vessel integrity and is essential for normal membrane fluidity [26].

Our results agree with those of Vaulthey et al. [26], who found that higher levels of total cholesterol were associated with better prognosis in early phases of acute ischemic cerebrovascular stroke. Other studies suggested that total cholesterol and LDL-cholesterol have an influence on the development of stroke caused by small vessel occlusion than on disease [27],[28].

In addition, the results of the present study showed a significant elevation of blood glucose in ICAD patients. This may be stress hyperglycemia due to the release of cortisol and norepinephrine, also a manifestation of relative insulin deficiency, as a result of diabetes. This hyperglycemia may exert direct cell membrane lipid peroxidation and cell lysis, which may be considered a pathology of ICAD [18].

Although the ferritin levels of patients before occurrence of acute stroke remains unknown, it is not understood whether the increase in serum ferritin levels occurs secondary to stress during the first hours of stroke or whether it is only a reflection of iron storage in the body tissues. Therefore, in our study, another classic stroke marker, CSF Aβ1-42 level, was also measured, and the relationship between the levels of CSF Aβ1-42 and both serum and CSF ferritin was determined. However, there was no correlation between CSF Aβ1-42 and ferritin levels in serum/CSF. Similarly in other studies, no correlation was established between ferritin and cortisol, which reflects the stress reaction of the acute phase of stroke [23],[24].

Serum ferritin level was found to be increased after the first 24 h in pharmacologically induced stress [26]. Moreover, in other studies, serum ferritin level was reported to be independent of stress that increases in the first week of stroke [24],[29].

Therefore, the increased serum ferritin level might indicate the severity of stroke and is correlated with the size of the lesion rather than being a stress-induced response. However, we did not study the course of serum ferritin level in this study. The serum ferritin level measured within the first 24 h could provide some information about the prognosis and prediction of clinical improvement.

The results of the present study revealed the existence of a link between atherosclerosis and oxidative stress triggered by transition metals. This agrees with the results of previous studies, which suggested that disturbed transition metal homeostasis, such as increased iron, zinc, and manganese, resulted in redistribution of metals between the brain and biological fluids responsible for supplying and clearing excreted metals from the brain. Accordingly, the levels of several regulatory and storage proteins of copper and iron are altered in patients with cerebral atherosclerosis [30],[31]. Moreover, Yang et al. [11] conducted a study on Wistar rats administered Tanshinone IIA; they concluded that it protected brain tissues against ischemic and hypoxic damage. They also suggested that maintaining brain iron homeostasis may be a novel therapeutic approach for ischemic cerebrovascular diseases. Another study suggested that treatment with clioquinol loosens amyloid plaques and aggregates and thus solubilizes smaller Aβ oligomers that would otherwise exert toxicity and become sequestered into amyloid deposits [32].

In conclusion, our results support the fact that elevated levels of CSF and serum ferritin may indicate a poor prognosis in terms of neurologic deterioration in ICAD-induced stroke patients. Elevated serum ferritin level correlates with both the severity of stroke and the size of lesion. Thus, serum ferritin level determined within the first 24 h after the onset of stroke may provide information that could help to predict the prognosis of stroke together with other clinical parameters and direct an extensive search for ICAD lesions.

A limitation of our study was the small number of patients included, especially those with good recovery. Thus, further studies with a larger number of patients are needed to elucidate the role of ferritin and iron and other trace metal metabolism in different etiological cerebrovascular diseases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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