Serum Alkaline Phosphatase and Phosphate in Cerebral Atherosclerosis and Functional Outcomes After Cerebral Infarction
Background and Purpose—Higher serum alkaline phosphatase (ALP) and phosphate levels are associated with atherosclerotic disease and an increased risk of cardiovascular events. However, the association of ALP/phosphate with cerebral atherosclerosis and prognosis in patients with acute stroke is not well known.
Methods—In 1034 patients with first-ever acute cerebral infarction, levels of ALP and phosphate were compared with (1) cerebral atherosclerosis and (2) poor long-term functional outcomes as defined by the modified Rankin Scale >2 at 3 months after stroke onset.
Results—ALP levels were not associated with cerebral atherosclerosis. However, higher levels of ALP were associated with a poor functional outcome (adjusted odds ratio per 1 SD, 1.25; 95% confidence interval, 1.04–1.50). Phosphate was associated with neither cerebral atherosclerosis nor functional outcome.
Conclusions—A higher level of ALP was not associated with cerebral atherosclerosis but was an independent prognostic factor for long-term functional outcome after acute cerebral infarction.
Serum levels of alkaline phosphatase (ALP) and phosphate are primarily used as markers of liver disease or bone disease in clinical practice. Recent epidemiological studies have demonstrated that elevated ALP or phosphate levels are associated with the presence of atherosclerosis in coronary and peripheral arteries, increased cardiovascular events, and mortality.1–5 ALP and phosphate are also considered to be surrogate markers of systemic inflammation, malnutrition, and metabolic syndrome, which may lead to worse clinical outcomes in patients with stroke.1,3 Therefore, we investigated whether ALP/phosphate is associated with cerebral atherosclerosis and long-term functional outcomes in patients with acute cerebral infarction.
This was a hospital-based, retrospective observational study. Candidates were patients admitted with a first-ever acute cerebral infarction. Patient inclusion and exclusion criteria are shown in Figure I in the online-only Data Supplement. Serum ALP and phosphate levels were measured at admission using peripheral venous blood with a Hitachi 7600-210 automatic analyzer (HITACHI, Tokyo, Japan). We collected data, including baseline characteristics, National Institutes of Health Stroke Scale score at admission, risk factors, and laboratory findings.
Cerebral atherosclerosis was defined as occlusion or significant stenosis (≥50%) of cerebral artery on the basis of digital subtraction angiography, magnetic resonance angiography, or computed tomographic angiography. The presence of cerebral atherosclerosis was assessed in intracranial cerebral arteries (anterior cerebral, middle cerebral, posterior cerebral, basilar, intracranial internal carotid, and intracranial vertebral arteries) and extracranial cerebral arteries (extracranial internal carotid and extracranial vertebral arteries). Then, patients were subdivided into 4 groups according to the location of cerebral atherosclerosis (no atherosclerosis, only intracranial, only extracranial, and both intracranial and extracranial atherosclerosis). We also collected data for the presence of coronary artery disease and peripheral artery disease. We defined a poor functional outcome as a modified Rankin Scale score of >2 at 3 months after stroke onset. Definition of risk factors, collected data, and statistical methods is shown in the Methods in the online-only Data Supplement. The Institutional Review Board of Severance Hospital, Yonsei University Health System, approved this study and waived the need for informed consent because of the retrospective and observational nature of the study.
Of the 1043 patients, 62.51% were men, and their mean age was 65.82±12.79 years. Mean values were 62.45±19.61 U/L for ALP and 1.07±0.21 mmol/L for phosphate. Clinical characteristics and their associations with ALP/phosphate are shown in Tables I and II in the online-only Data Supplement. ALP was associated with old age, higher frequency of hypercholesterolemia, and higher hemoglobin, cholesterol, alanine aminotransferase, and glucose. Phosphate was associated with female sex, lower National Institutes of Health Stroke Scale score at admission, higher cholesterol, triglyceride, and calcium, and lower hemoglobin and high-sensitivity C-reactive protein.
There were 623 patients (59.73%) with cerebral atherosclerosis. The levels of ALP/phosphate were not associated with intracranial or extracranial cerebral atherosclerosis (Table 1). When we subdivided patients according to the degree of cerebral atherosclerosis (no atherosclerosis, <50%, 50%–75%, and ≥75% or occlusion), there was no significant difference of ALP/phosphate among them (Table III in the online-only Data Supplement).
At 3 months, 243 patients (23.3%) showed poor functional outcomes. Elevated ALP levels were associated with a poor functional outcome (61.17±17.24 versus 66.66±25.51 U/L; P=0.002), but phosphate levels were not (1.07±0.20 versus 1.07±0.22 mmol/L; P=0.826). After adjustment for sex, age, and other covariates that had a P<0.05 on univariate analysis (Table IV in the online-only Data Supplement), odds ratio for 1 increase of SD in ALP (19.61 U/L) was 1.25 (95% confidence interval, 1.04–1.50; P=0.017; Table 2). Penalized-spline curve demonstrated a positive relationship between levels of ALP and an increased risk for poor functional outcomes (Figure).
In this study, we tested the hypothesis that elevated ALP/phosphate levels are associated with cerebral atherosclerosis, which was based on previous reports that showed a higher prevalence of coronary artery disease and peripheral artery disease in patients with elevated ALP/phosphate levels. However, such a relationship between serum ALP/phosphate levels and cerebral atherosclerosis was not found in our study. The action of ALP/phosphate might differ in each vascular bed. Susceptibility to atherosclerosis is strongly influenced by intrinsic differences in the cells composing each vascular system.6 Associated risk factors and pathological findings, including calcification, differ according to the location of the atherosclerosis. Although we defined atherosclerosis as significant stenosis (≥ 50%) on angiographic studies, most previous studies used definitions based on coronary artery calcium score, ankle-brachial index, and carotid intima thickness. ALP and phosphate are suggested to enhance medial calcification and stiffening of the vessel and further atherosclerosis.5,7 Medial calcification has a longitudinal, uniform distribution (pipeline-like) without focal luminal narrowing.6 Thus, ALP-/phosphate-related medial calcification and atherosclerosis might be undetected in angiographic studies.
Inflammation may be a link between elevated ALP levels and poor clinical outcomes.3,4 ALP is increased in inflammatory conditions, poor nutrition, and infections, which could lead to worse functional outcomes after stroke.3,8 In contrast to ALP, phosphate is not associated with functional outcomes in this study. Although there are reports for increased mortality with high levels of serum phosphate, low levels of phosphate are also associated with malnutrition, low physical activity, hypertension, and metabolic syndrome.3,9 Racial differences and genetic polymorphisms among Western and Asian individuals might be present.5 Compared with Asian diets, Western diets are relatively high in bioavailable phosphate.5 The lack of an association in this study between phosphate and functional outcomes in Asian patients with stroke may be partly ascribed to the complex nature of phosphate.
This study has some limitations. Selection bias might be present because this was a retrospective observational study in a single center, and many patients were excluded because of missing data. The mechanism behind the association between elevated ALP and poor functional outcomes is unclear. We could not conclude whether elevated ALP caused poor outcomes or was only a marker for stroke prognosis. Other potential factors, such as alcohol consumption, not collected in this study might act as confounders.
We did not find a significant association between serum ALP/phosphate and cerebral atherosclerosis. Patients with elevated ALP levels had poor functional outcomes after acute cerebral infarction.
Sources of Funding
This work was supported by a grant from the Korea Healthcare Technology Research and Development Project, Ministry for Health and Welfare, Republic of Korea (HI10C2020).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.113.002959/-/DC1.
- Received July 23, 2013.
- Accepted August 15, 2013.
- © 2013 American Heart Association, Inc.
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