Hindawi

Journal of Healthcare Engineering

Volume 2022, Article ID 9711712, 6 pages
https://doi.org/10.1155/2022/9711712

Research Article
High-Sensitivity C-Reactive Protein and Ischemic Stroke in
Patients with Nonalcoholic Fatty Liver Disease:
A Prospective Study

Meng Jia,1 Yingxin Shi,2 Yuemeng Wang,3 Mei Wang,1 Liang Zhang,2
Qingjuan He,3 and Tao Yuan 1
1
Department of Geriatrics, Qingdao Eighth People’s Hospital, Qingdao, Shandong 266121, China
2
Intensive Care Unit, Qingdao Eighth People’s Hospital, Qingdao, Shandong 266121, China
3
Department of Gastroenterology, Qingdao Eighth People’s Hospital, Qingdao, Shandong 266121, China

Correspondence should be addressed to Tao Yuan; [email protected]

Received 3 November 2021; Accepted 14 December 2021; Published 30 March 2022

Academic Editor: Kalidoss Rajakani

Copyright © 2022 Meng Jia et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background and Aims. Inflammation is involved in the pathophysiology of ischemic stroke. The aim of this prospective study was
to evaluate the association of hs-CRP with incident ischemic stroke in patients with nonalcoholic fatty liver disease (NAFLD).
Methods. A sample of 318 participants without previous strokes was included in this study. Hs-CRP levels and other potential
confounding factors were measured at baseline. NAFLD was performed by abdominal ultrasound after excluding secondary
causes for fat accumulation. According to baseline hs-CRP concentrations, participants were categorized into 3 groups: level 1
(<1.0 mg/L), level 2 (1.0 to <3.0 mg/L), and level 3 (≥3.0 mg/L). The outcome of interest was the first occurrence of an ischemic
stroke. Cox proportional hazards models were used to analyze hazard ratios (HRs) and 95% confidence intervals (CIs) of incident
ischemic stroke, after adjusting for potential confounders. Results. The mean age of 318 participants with NAFLD was 71.1 ± 6.7
years, and 55.3% of them were male. Among 318 individuals with NAFLD, 115 (36.2%) of them had an hs-CRP value <1 mg/L
(level 1), 105 (33.0%) had an hs-CRP value between 1 and 3 mg/L (level 2), and 98 (30.8%) belonged to level 3 (hs-CRP ≥3 mg/L).
Over a median of 5.60 years of follow-up, 47 incident ischemic stroke events were documented in 318 patients with NAFLD. After
full adjustment for confounding factors, compared with participants in the level 1 group (hs-CRP<1.0 mg/L), the HRs of those in
the level 2 group (1.0 to <3.0 mg/L) and the level 3 group (≥3.0 mg/L) were 1.77 (95% CI: 0.94–2.98) and 2.45 (95% CI: 1.37–5.77)
for developing ischemic stroke, respectively. Conclusions. Elevated hs-CRP levels were associated with an increased risk of
ischemic stroke among patients with NAFLD.

1. Introduction countries [3]. Thus, the need to take more efficient stroke
prevention and treatment strategies is urgent. Nonalcoholic
Ischemic stroke approximately accounts for 70–80% of fatty liver disease (NAFLD), a common cause of liver disease,
strokes, which is the second most common cause of death could be an independent risk factor for future ischemic
and the third most common cause of disability in the world stroke [4]. The prevalence of NAFLD is 25.24% globally, with
[1]. In 2013, there were almost 18.3 million patients with many metabolic comorbidities including obesity (51.34%),
previous ischemic stroke, 3.3 million deaths from ischemic type 2 diabetes (22.51%), dyslipidemia, and metabolic
stroke, and 6.9 million new ischemic strokes worldwide [2]. syndrome [5]. A recent meta-analysis with 34,043 adult
An international study of stroke costs shows that the esti- individuals demonstrated that patients with NAFLD were
mated expenditure for stroke was about 3% of total health more likely to have incident fatal and nonfatal cardiovas-
care expenditures, which is similar among eight developed cular disease events [6]. Furthermore, a better
2 Journal of Healthcare Engineering

understanding of the potential mechanism between NAFLD 658 patients enrolled

and ischemic stroke might have important clinical impli- in the cohort

cations for future healthcare policies.

619 patients with baseline
Inflammation response is likely to play an essential role examination completed
in the pathogenesis and progression of ischemic stroke [7].
Exclude: Missing data:
C-reactive protein (CRP) using a high-sensitivity assay Patients with previous Abdominal ultrasound
(high-sensitivity CRP, hs-CRP), a low-grade chronic in- ischemic stroke (n=27) (n=102)
Patients with excessive
flammation biomarker, has been demonstrated to be asso- alcohol consumption hs-CRP (n=45)
ciated with an increased risk of ischemic stroke [8]. CRP, an (n=112)
Patients los of follow-up
acute-phase reactive protein, is a blood constituent of the (n=15)
pentraxin family and is synthesized by the liver [9]. CRP is 318 patients with NAFLD
thought to be involved in activating platelets and comple- included in this study
ment proteins by interacting with other mediators [10, 11]. A Figure 1: Flowchart of this study.
meta-analysis of 54 long-term prospective studies indicated
that the risk ratio (RR) of per standard deviation higher
log(e) CRP was 1.27 (1.15–1.40) for ischemic stroke after seated silently for 15 minutes, systolic blood pressure (SBP)
adjusting for conventional risk factors [12]. A case-control and diastolic blood pressure (DBP) were measured by using
study of 472 strokes showed that the adjusted odds ratio an automatic blood pressure meter. Venous blood samples
(OR) of the last third of CRP level was 1.39 (95% CI: were drawn in the morning after an 8-hour overnight fast.
1.05–1.85) for recurrent ischemic stroke [13]. By contrast, Blood levels of alanine transferase (ALT), aspartate trans-
the Northern Manhattan Study (NOMAS) of 2,240 stroke- ferase (AST), total cholesterol (TC), triglyceride (TG), low-
free community participants suggested that hs-CRP could density lipoprotein cholesterol (LDL-C), high-density li-
predict mortality but not ischemic stroke [14]. Conse- poprotein cholesterol (HDL-C), creatinine, and uric acid
quently, the controversial evidence of hs-CRP in ischemic (UA) were measured by using an AutoAnalyzer (Hitachi
stroke makes the role of hs-CRP levels in the clinical setting 747; Japan) at the clinical laboratory of a local hospital. The
remain unclear. concentration of hs-CRP was assessed by high-sensitivity
The objective of this study is to examine the association nephelometry assay (Cias Latex CRP-H; Japan). The lower
of hs-CRP levels with the occurrence of ischemic stroke limit of detection was 0.10 mg/L. The intraassay coefficient of
among patients with nonalcoholic fatty liver disease, after variation was 6.5%, and the interassay coefficient of variation
adjusting for potential confounding factors. was 4.8%.

2. Methods 2.3. Assessment of NAFLD. NAFLD was defined as hepatic

steatosis assessed by abdominal ultrasound without causes
2.1. Study Population. The current study was a hospital- for secondary fat accumulation. Abdominal ultrasound was
based prospective cohort study aiming to investigate the performed by well-trained radiologists who were blinded to
relationship between NAFLD and ischemic stroke. From clinical characteristics and laboratory tests. Excessive alcohol
April 2009 to June 2011, participants aged ≥18 years were intake was determined as >210 g/week in men and >140 g/
recruited from the outpatient department in our hospital. week in women based on the guideline recommendation
After excluding patients with acute infection, unknown [15].
fever, cancer, autoimmune diseases, severe kidney and liver
dysfunction, hypercoagulable state, or hematological dis-
eases, 658 patients were eligible for the study. Each par- 2.4. Follow-Up and Ischemic Stroke Ascertainment. From the
ticipant was scheduled to undergo a baseline survey, baseline survey, the follow-up of study participants was
including questionnaire evaluation, physical examinations, continued until the incidence of stroke, or June 30, 2019,
biochemical tests, and abdominal ultrasound. The details of whichever came first. We contacted study participants or
318 patients with NAFLD enrolled in the analysis are shown their authorized persons by interview or telephone every
in Figure 1. year. The outcome of interest was the first occurrence of an
All participants have signed informed consent. This ischemic stroke. The ascertainment of ischemic stroke was
study protocol was approved by the ethics committee of local determined by an experienced clinician after a systematic
hospital. review of clinical symptoms, physical signs, and brain
computed tomography scans or magnetic resonance
imaging.
2.2. Baseline Data Collection. Participants’ information was
obtained by using standard questionnaires, including age,
sex, smoking status, alcohol consumption, and disease 2.5. Statistical Analysis. All patients were categorized into
history (such as hypertension, diabetes, and dyslipidemia). three groups according to hs-CRP concentrations: level 1
Each participant underwent a physical examination of (<1.0 mg/L), level 2 (1.0-<3.0 mg/L), and level 3 (≥3.0 mg/L)
height and weight, and BMI was calculated by body weight [8]. Categorical variables were described by frequencies and
(kg) divided by height square (m2). After participants were percentages, and compared using chi-squared tests.
Journal of Healthcare Engineering 3

Continuous variables with a skewed distribution were Breslow test P < 0.001), indicating that the mean time for
expressed as median (25% and 75%) and compared using the incident ischemic stroke event in NAFLD patients with hs-
Kruskal–Wallis test. Continuous variables with normal CRP concentration ≥3 mg/L was significantly shorter
distributions were presented as mean ± standard deviation compared to NAFLD patients with hs-CRP concentration
(SD) and compared using the student’s t-test or the 1-way <3 mg/L (Figure 2).
ANOVA test. Kaplan–Meier curves were used to present the In a Cox proportional hazards analysis with patients in
time to incident ischemic stroke event for each hs-CRP level 1 as the reference group, the patients with hs-CRP in
group. We used Cox proportional hazards models to esti- level 3 were independently associated with the high risk of
mate the independent association of hs-CRP levels with the ischemic stroke (Table 3). Compared to participants with hs-
occurrence of ischemic stroke, after adjusting for potential CRP <1 mg/L (level 1), the adjusted HRs for the risk of
confounding factors in three models, respectively. The po- ischemic stroke was 2.07 (95% CI: 0.90–4.72) in the level 2
tential confounding factors included age, gender, BMI, group and 3.30 (95% CI: 1.52–7.14) in the level 3 group, after
history of hypertension, diabetes, dyslipidemia, SBP, DBP, adjusting age and gender in model 1 (P for trend � 0.006).
TC, TG, LDL-C, ALT, AST, creatinine, and UA. A signif- Model 2 adjusted for model 1 and for BMI, history of hy-
icant level was set as P < 0.05 (2-sided). Statistical analyses pertension, diabetes, and dyslipidemia. After adjusting for a
were performed with IBM SPSS Statistics 21.0. series of potential confounding factors in model 3, the
adjusted HR for patients with hs-CRP of 1 to <3 mg/L was
3. Results 1.77 (95%CI, 0.94–2.98), and the adjusted HR for patients
with hs-CRP >3 mg/L was 2.45 (95%CI, 1.37–5.77) com-
658 patients were enrolled in the study, but only 619 patients pared to patients with hs-CRP <1 mg/L (P for trend � 0.011).
completed the baseline examination (Figure 1). We excluded
147 subjects without abdominal ultrasound data (n � 102) 4. Discussion
and hs-CRP values (n � 45), 27 patients with previous is-
chemic stroke, 112 patients with excessive alcohol con- In this prospective study of 318 patients with NAFLD, after a
sumption, and 15 patients who lost follow-up. Finally, a total median of 5.6 years of follow-up, we observed an inde-
of 318 patients with nonalcoholic fatty liver disease were pendent association of hs-CRP level with the occurrence of
included in the study (Figure 1). ischemic stroke. High hs-CRP concentration was signifi-
The mean age of 318 participants with NAFLD was cantly associated with elevated risk of ischemic stroke, after
71.1 ± 6.7 years, and 55.3% of them were male. Baseline adjusting a series of potential confounding factors including
characteristics of the study participants based on the hs-CRP demographic characteristics, medical history, and metabolic
levels are shown in Table 1. Among 318 individuals with parameters. Our results support the validity of circulating
NAFLD, 115 (36.2%) of them had an hs-CRP value <1 mg/L hs-CRP as a clinical biomarker to detect subjects at high risk
(level 1), 105 (33.0%) had an hs-CRP value between 1 and of ischemic stroke who are likely to benefit from primary
3 mg/L (level 2), and 98 (30.8%) belonged to level 3 (hs-CRP prevention strategies among patients with NAFLD.
≥3 mg/L). Compared with patients in level 1, patients in level The association of hs-CRP and ischemic stroke in our
3 were more likely to be older, have a higher BMI, and have a study was in accordance with the findings in the Cardio-
history of hypertension and dyslipidemia. Individuals with vascular Health Study. The Cardiovascular Health Study of
hs-CRP ≥3 mg/L had a higher level of blood pressure, TC, 5417 individuals aged 65 years or older without previous
LDL-C, and serum UA than individuals with hs-CRP stroke, after 10.2 years of follow-up, found that the adjusted
<1 mg/L. However, there was no significant difference HR in the 4th quartile of CRP level was 1.60 (95% CI:
among participants in three hs-CRP subgroups in the 1.23–2.08) for ischemic stroke relative to the 1st quartile
proportion of gender, diagnosed diabetes, and the con- [16]. In addition, an international, multicenter, prospective
centration of TG, HDL-C, ALT, AST, and creatinine. study indicated that, after adjusting for demographics
Table 2 shows the hs-CRP levels in different subgroups. characteristics and risk factors, patients with hs-CRP
Participants aged ≥75 years had higher hs-CRP levels of 2.37 >4.86 mg/L (the top quartile) were at elevated risk of re-
(1.01, 3.73) than participants aged <65 years. Besides, sub- current ischemic stroke (adjusted HR: 2.32; 95% CI:
jects with a BMI ≥28 kg/m2 had higher hs-CRP levels of 2.79 1.15–4.68) [17]. Other studies relating CRP levels to ischemic
(2.07, 4.51) than subjects with a BMI <24 kg/m2. The levels of stroke have shown contrary results. The Northern Man-
hs-CRP were not significantly associated with hypertension. hattan Study (NOMAS) showed that, compared with
However, the levels of hs-CRP were higher with prevalent community participants with hs-CRP <1 mg/L, the adjusted
diabetes and dyslipidemia. HR of those with hs-CRP >3 mg/L was 1.20 (95% CI:
After a median follow-up of 5.60 years, we identified 47 0.78–1.86) for an elevated risk of ischemic stroke [14].
incident ischemic stroke events among 318 patients with Moreover, a previous study of 467 patients with first is-
nonalcoholic fatty liver disease. The Kaplan–Meier curve chemic stroke revealed that hs-CRP level was not associated
revealed that NAFLD patients with higher hs-CRP levels with the occurrence of recurrent stroke after adjusting for
appeared to separate from the other groups throughout the confounders [18]. The variation between these earlier studies
follow-up period (Figure 2). The Logrank and Breslow tests is likely attributed to differences in sample size, different
suggested that the survival distributions of these three cutoff points of hs-CRP, selection of study populations, and
groups differed significantly (Logrank test P � 0.006; the prevalence of comorbid conditions.
4 Journal of Healthcare Engineering

Table 1: Baseline characteristics of the study participants according to hs-CRP levels.

Baseline hs-CRP group
Variables P value
Level 1 (<1 mg/L) Level 2 (1 to <3 mg/L) Level 3 (≥3 mg/L)
n 115 105 98 —
Age, y 69.7 ± 6.8 71.2 ± 5.9 72.1 ± 7.2 0.021
Male, n (%) 65 (56.5) 57 (54.3) 54 (55.1) 0.073
BMI, kg/m2 24.1 ± 2.7 25.4 ± 3.1 25.1 ± 3.7 0.032
Hypertension, n (%) 41 (35.7) 37 (35.2) 40 (40.8) 0.003
Diabetes, n (%) 15 (13.0) 17 (16.2) 14 (14.3) 0.104
Dyslipidemia, n (%) 44 (38.3) 31 (29.5) 47 (48.0) <0.001
SBP, mmHg 132.5 ± 17.1 136.7 ± 14.2 143.1 ± 16.8 0.007
DBP, mmHg 71.3 ± 11.2 75.4 ± 10.7 78.2 ± 13.1 0.003
TC, mmol/L 4.71 ± 1.07 5.13 ± 1.45 5.92 ± 1.41 <0.001
TG, mmol/L 1.59 (0.88, 2.04 1.73 (0.75, 2.17) 1.64 (1.09, 2.21 0.129
HDL-C, mmol/L 1.02 ± 0.31 0.95 ± 0.41 0.89 ± 0.37 0.251
LDL-C, mmol/L 2.71 ± 0.55 2.99 ± 0.74 3.41 ± 0.42 <0.001
ALT, IU/L 21.3 ± 13.7 22.6 ± 11.6 24.5 ± 8.7 0.322
AST, IU/L 22.1 ± 9.2 24.1 ± 8.8 23.4 ± 7.9 0.211
Creatinine, μmol/L 70.5 ± 22.1 73.4 ± 19.5 74.5 ± 20.2 0.105
UA, μmol/L 321.2 ± 95.4 344.9 ± 79.4 364.4 ± 88.5 <0.001
hs-CRP, mg/L 0.68 (0.37, 0.81) 1.74 (1.21, 2.31) 4.74 (3.91, 6.22) <0.001
BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; TC, total cholesterol; TG, triglyceride; LDL-C, low density lipoprotein
cholesterol.

Table 2: Comparisons of hs-CRP levels by different subgroups. Ischemic Stroke

40
Cumulative incidence (%)

hs-CRP, mg/L
P value
Median (interquartile range)
Age, y 0.032 30
<65 1.49 (0.74, 2.01) Logrank p = 0.006
65 to <75 1.73 (0.92, 2.34)
Breslow p < 0.001
≥75 2.37 (1.01, 3.73) 20
Gender 0.304
Male 1.82 (0.91, 2.41)
Female 1.74 (0.89, 2.33) 10
BMI, kg/m2 <0.001
<24 1.01 (0.41, 1.42)
24 to <28 1.74 (0.71, 2.32) 0
≥28 2.79 (2.07, 4.51) 0 2 4 6 8 10
Hypertension 0.087 Time (years)
Yes 2.47 (0.91, 3.44)
No 1.98 (1.14, 2.99) level 1
Diabetes 0.013 level 2
Yes 2.59 (1.08, 3.07) level 3
No 1.71 (0.92, 2.49) Figure 2: Kaplan–Meier curves of incident ischemic stroke by
Dyslipidemia <0.001 different hs-CRP levels.
Yes 2.19 (0.94, 3.11)
No 1.48 (0.71, 2.41)
BMI, body mass index. endothelial cells and inducing tissue factor secretion in
monocyte-macrophages [20].
The association between hs-CRP and ischemic stroke
This observational study could not address the potential was examined in an apparently healthy population [21], in
mechanisms of hs-CRP in ischemic stroke, but there are participants with hypertension and diabetes [22], but not
several studies supporting an underlying link between hs- well established in patients with NAFLD. Our study in
CRP and ischemic stroke. CRP might be involved in the patients with NAFLD is consistent with a previous pro-
pathogenesis of chronic ischemia by quenching the pro- spective study, which showed elevated gamma-glutamyl-
duction of nitric oxide (NO) and inhibiting angiogenesis transferase (GGT) levels, mostly due to NAFLD, are
[19]. Besides, CRP has been documented to play an im- associated with an increased risk of stroke independent of
portant role in atherogenesis by elevating the levels of established cardiovascular risk factors [23]. A prospective
endothelin-1, cell adhesion molecules, and interleukin-8 in cohort study further demonstrated that, after a median of
Journal of Healthcare Engineering 5

Table 3: Hazard ratios (HRs) for ischemic stroke by different hs-CRP levels.
Baseline hs-CRP group
P for trend
Level 1 (<1 mg/L) Level 2 (1 to <3 mg/L) Level 3 (≥3 mg/L)
Cases, n 9/115 15/105 23/98 —
Incidence rate 7.83 14.29 23.47 —
Model 1, HR (95% CI) Reference 2.07 (0.90, 4.72) 3.30 (1.52, 7.14) 0.006
Model 2, HR (95% CI) Reference 1.98 (0.92, 3.15) 2.97 (1.43, 6.51) 0.009
Model 3, HR (95% CI) Reference 1.77 (0.94, 2.98) 2.45 (1.37, 5.77) 0.011
Model 1: adjusted for age and gender. Model 2: adjusted for Model 1 and for BMI, history of hypertension, diabetes, and dyslipidemia. Model 3: based on
model 2, further adjusted for SBP, DBP, TC, TG, LDL-C, ALT, AST, creatinine, and UA.

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