Section of Neurology,
Hospital Universitari Doctor Josep Trueta,
Girona, Spain
Section of Endocrinology,
Hospital Universitari Doctor Josep Trueta,
Girona, Spain
Service of Neurology,
Hospital Xeral de Galicia,
Santiago de Compostela, Spain
To the Editor:
Three major molecular events in brain damage from cerebrovascular
occlusion are at present the focus of interest: calcium overload,
excessive acidosis, and enhanced production of free radicals.
Free radicals are generated in increased amounts under ischemic
conditions and react with and damage proteins, nucleic acids, and
membrane lipids, disrupting cellular integrity.1 This
oxygen radical activity is especially intense during reperfusion after
sustained ischemia. The generation of radical hydroxyl, the
most toxic and reactive of free radicals, is catalyzed by ferrous iron
released from intracellular stores during ischemia; thus, the
sensitivity of neurons to oxidative stress depends on the availability
of iron in the ischemic focus.2 3 Iron is released
from large transport proteins, particularly from ferritin, which
accounts for one third to three quarters of brain iron.4
In the absence of inflammation, cancer, and infectious diseases, the
serum concentration of ferritin is thought to be directly proportional
to tissue iron stores and can be used to assess their
size.5
Despite the theoretical importance of iron in oxidative brain
injury, very little direct evidence exists to implicate iron in stroke.
In experimental models, iron depletion or chelation reduces
ischemia-reperfusion–induced edema and metabolic
failure.6 7 We found in 67 patients with acute
ischemic stroke that high serum ferritin levels within the
first 48 hours after stroke onset were associated with a poor
prognosis, independent of the stress response.8 Using the
same protocol, we have recently reproduced these results in a different
and larger series of 103 patients (A. Dávalos, personal
communication, European Stroke Conference, Amsterdam, the Netherlands,
1997). Median serum ferritin concentrations were 383 µg/L (quartiles,
158 and 442) in 40 patients with poor outcome and 218 µg/L
(quartiles, 129 and 345) in 63 with good outcome (P=.004).
Because ferritin concentrations in both studies were measured only
once, usually several hours after stroke onset, an early increase due
to the acute-phase response was not completely ruled out. The aim of
this study was to demonstrate that serum ferritin concentrations were
not modified during the acute phase (5 days) of ischemic stroke
and that they were not related to stress and inflammatory
reactions.
We studied prospectively a group of 34 consecutive patients (mean
age 69±8 years; 14 males and 20 females) with an acute
ischemic stroke of <8 hours in duration. Blood samples were
collected at admission (mean time from stroke onset, 4.9±1.4 hours);
at 12, 24, and 48 hours; and at day 5 from the onset of symptoms.
Laboratory parameters measured for the purpose of this
study were serum ferritin, cortisol, and C-reactive protein. In
addition, leucocyte count and plasma fibrinogen were determined in the
first blood sample. Diabetes was recorded in 9 patients,
hypertension in 16, atrial fibrillation in 12, and ischemic
heart disease in 2. The type of stroke was large-artery
atherothrombotic infarct in 12 patients, cardioembolic in 11, lacunar
in 6, and of unknown origin in 5. The mean Canadian Stroke Scale score
at admission was 5.5±2.7. One patient died on the second day of
hospitalization, and 6 patients had infectious or inflammatory diseases
during the 5-day study period.
Comparisons for paired measures (Wilcoxon rank test)
showed no statistical differences between the concentrations of
ferritin at admission and those obtained at each time interval during
the first 48 hours, whereas cortisol values decreased significantly and
C-reactive protein showed a moderate increase after the first 24 hours
from stroke onset (Figure
Our results confirm that serum ferritin concentrations are not
associated with the stress reaction and the acute phase response. The
nonsignificant rise in serum ferritin during the first 2 days after
stroke is of insufficient magnitude to explain the large difference in
ferritin levels between the patients with good prognoses and those with
bad prognoses reported by our group.8 These findings
suggest that serum ferritin can provide a reliable index of iron stores
in acute stroke patients without infectious or inflammatory diseases.
Therefore, the association between increased concentrations of ferritin
and poor outcome found in our previous investigations could be
attributed to a potentially increased availability of iron in the
ischemic area. A later increase of ferritin in some patients
after the second day was consistent with stroke comorbidity.
However, serum ferritin may be primarily an indicator of other vascular
risk factors themselves related to stroke prognosis. Iron overload may
elevate the risk of atherosclerotic diseases by promoting the oxidation
of LDL cholesterol.9 High serum ferritin
concentrations in the early acute phase of stroke could also result
from inflammatory changes or infections preceding cerebral
ischemia that have been recognized as risk factors for stroke
and transient ischemic attack.10 Nevertheless, in
this study the lack of association of serum ferritin on admission with
other analytical parameters such as leucocyte count,
fibrinogen, and C-reactive protein, which have been all related to
previous chronic inflammation in patients with ischemic
vascular diseases,11 makes this mechanism improbable.
Serum ferritin determination should be included in future
investigations on prognostic factors in acute ischemic
stroke.
References
1.
Schmidley JW. Free radicals in central
nervous system ischemia. Stroke.. 1990;25:7-12.
2.
Reif DW. Ferritin as a source of iron for
oxidative damage. Free Radic Biol Med.. 1992;12:417-427.[Medline]
[Order article via Infotrieve]
3.
Chan PH. Role of oxidants in ischemic
brain damage. Stroke.. 1996;27:1124-1129.
4.
Connor JR. Cellular and regional
maintenance of iron homeostasis in the brain: normal and
diseased states. In: Riederer P, Youdin MBH, eds. Iron in
Central Nervous System Disorders. Springer-Verlag/Wien, New York,
NY: 1993:1-18.
5.
Salonen JT. The role of iron as a
cardiovascular risk factor. Curr Opin
Lipidol.. 1993;4:277-282.
6.
Patt A, Horesh IR, Berger EM, Harken AH, Repine JE.
Iron depletion or chelation reduces
ischemia/reperfusion-induced edema in gerbil brains.
J Pediatr Surg.. 1990;25:224-228.[Medline]
[Order article via Infotrieve]
7.
Davis S, Helfaer MA, Traystman RJ, Hurn PD.
Parallel antioxidant and antiexcitotoxic therapy improves
outcome after incomplete global cerebral ischemia in
dogs. Stroke.. 1997;28:198-205.
8.
Dávalos A, Fernandez-Real JM, Ricart W, Soler S,
Molins A, Planas E, Genís D. Iron-related damage in
acute ischemic stroke. Stroke.. 1994;25:1543-1546.[Abstract]
9.
Salonen JK, Nyssönen K, Korpela H, Tuomilehto J,
Seppänen R, Salonen R. High stored iron levels are
associated with excess risk of myocardial infarction in eastern Finnish
men. Circulation.. 1992;86:803-811.
10.
Grau A, Buggle F, Heindl S, Steichen-Wiehn C, Banerjee
T, Maiwald M, Rohlfs M, Suhr H, Fiehn W, Becher H, Hacke W.
Recent infection as a risk factor for cerebrovascular
ischemia. Stroke.. 1995;26:373-379.
11.
Grau A, Buggle F, Becher H, Werle E, Hacke W.
The association of leukocyte count, fibrinogen, and C-reactive
protein with vascular risk factors and ischemic vascular
diseases. Thromb. Res.. 1996;82:245-255.[Medline]
[Order article via Infotrieve]
© 1998 American Heart Association, Inc.
Letters to the Editor
Serum Ferritin Concentrations Are Not Modified in the Acute Phase of Ischemic Stroke
).
In those patients with infectious or inflammatory diseases, ferritin
concentrations were stable during the early acute phase but increased
significantly after 24 hours from stroke onset, as did C-reactive
protein. Ferritin values did not correlate with leucocyte count and
fibrinogen concentrations at inclusion (Spearman coefficients of .083
and .19, respectively; P=NS). The correlations between
ferritin values and cortisol and C-reactive protein values of each
sample obtained during the study period were not significant
(coefficients, <0.25; P=NS).
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Figure 1. Median values and quartiles of serum ferritin (top
panel), plasmatic cortisol (middle), and C-reactive protein (bottom)
concentrations at each interval from symptom onset in 34 patients with
acute ischemic stroke. Numbers indicate probability values
(Wilcoxon rank test) of the comparisons between the
concentrations of laboratory parameters at admission and
those obtained at each time interval.
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