Association between serum lipids and apolipoproteins level and chronic subdural hematoma: a case-control study

DOI: https://doi.org/10.21203/rs.3.rs-1692289/v1

Abstract

Background: Several studies, including a randomized clinical trial, have demonstrated that atorvastatin may be an effective nonoperative treatment for chronic subdural hematoma (CSDH). Atorvastatin is mainly used to regulate lipid metabolism. However, few studies investigated the association between serum lipids level and risk of CSDH.

Methods: We conducted a retrospective case-control study to assess the relationship between fasting lipids (total cholesterol, triglyceride, HDL-C and LDL-C), apolipoproteins (ApoA1, ApoB) and risk of CSDH. Using a one-to-three case–control ratio, 137 CSDH patients were included in our study. Conditional logistic regression was used to examine the relationship between lipids and apolipoproteins biomarkers and risk of CSDH.

Result: In univariate analysis, baseline levels of total cholesterol (P<0.001), HDL-C (P<0.001) and ApoA1 were significantly lower among patients with CSDH, while levels of ApoB were higher. No significant difference for triglyceride (P=0.15) and LDL-C (P=0.47) were observed. In multivariable analysis, total cholesterol (OR for the highest vs lowest quartile 0.34, 05%CI 0.19-0.64, P<0,001), triglycerides (OR 1.98, 95%CI 1.05-3.71, p<0,05), HDL-C (OR 0.26, 95%CI 0.13-0.52, P<0,001), ApoA1 (OR 0.27, 95%CI 0.14-0.52, P<0,001) were significantly associated with CSDH, when conditioned on age and gender, and adjusted for head trauma and hypertension. Additional adjustment for all covariates of interest don’t substantially change the multivariable associations.

Conclusion: Among a panel of lipids and apolipoproteins biomarkers, total cholesterol, triglycerides, HDL-C, ApoA1 were significantly associated with CSDH.

Introduction

Chronic subdural hematoma (CSDH) is a common neurosurgical condition in the elderly. With the progress of the population aging, the incidence of CSDH is increasing[1, 2]. Several risk factors for CSDH have been identified in many studies. The incidence of CSDH is more prevalent in males than in females[3]. Direct or indirect head trauma is considered the most common risk factor for CSDH[2, 4]. Besides, alcoholism, hypertension, chronic renal failure, anticoagulants and antiplatelet agents are also well known as causes of CSDH[58]. Surgery is currently considered to be the first line treatment for CSDH[2]. However, many people, especially the elderly, have obvious contraindications to surgery[9], so more and more scholars are trying to find non-surgical treatment for CSDH[10, 11].

Recently a series of studies, including a multi-center randomized, placebo-controlled, double-blind phase II clinical trial had indicated that atorvastatin may be a safe and efficacious nonsurgical alternative for treating patients with CSDH[1216]. The study indicated that atorvastatin could reduce hematoma volume and improve neurological function of the patients[12]. Atorvastatin is often used to lower blood levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides, to increase levels of high-density lipoprotein cholesterol (HDL-C)[17]. Recently, a survival analysis suggested that low level of HDL is significantly associated with recurrence of CSDH[18]. However, few studies explored whether serum lipids and apolipoproteins level are associated with the development of CSDH. We retrospectively investigated the association between lipids and apolipoproteins biomarkers and the risk of CSDH in a case-control analysis.

Methods

Study Participants

This retrospective study was based on medical documentation of 162 consecutive patients between January 2014 and November 2021 with first CSDH hospitalized and diagnosed in a single academic Department of Neurosurgery. CSDH was diagnosed using computed tomography, showing a crescent-shaped mass with a slight hypodensity or increased density or heterogeneous density[19]. Patients were excluded if they had repeated hospitalizations with CSDH or whose serum lipid was not available. Each case was independently evaluated by 2 authors (Che and Long) as having met these criteria. This study was approved by the Ethics Committee of the first Affiliated Hospital of Chongqing Medical University.

Sample Size and Controls

The required sample size was determined by assuming that 40% of Chinese adults with dyslipidemia with the relative risk of CSDH being 1.5. For a one-to-three case–control ratio at the 5% level of significance, the sample size needed to attain 90% power were 135 for case group and 405 for control group. A total of 137 patients with CSDH and 411 control subjects included the study. Those patients who were excluded from the study because fasting total serum cholesterol was not available, resembled those who were included.

Controls, matched for age (±2 years) and gender, were randomly selected from the patients who come from Department of Emergency Surgery in our hospital, and were excluded if they had stroke, coronary heart disease or treated with lipid-lowering agents. Patients with pancreatitis was also excluded, since studies had shown that dyslipidemia is associated with the development of pancreatitis[20]. Cases with head trauma were matched as closely as possible with controls with head trauma. If a potential control’s serum lipid was not available, another eligible control was selected.

Data Collection

   The information obtained from each study subject included demographic characteristics (age, gender, marital status), past medical history (including a history of hypertension, diabetes mellitus, malignant tumor, kidney failure and dementia), smoking habits, alcohol consumption, head trauma within 3mouth, anticoagulant. Alcohol consumption was classified as daily, occasional, never drinking or former drinking (abstaining for at least 1 year before the admission). Smoking status was categorized into current smokers (at least one cigarette per day), former smokers (abstaining for at least 1 year before the admission), and never smokers. Marital status is classified as married and unmarried (includes unmarried, widowed and divorced).

Laboratory Analyses

Data on lipid profiles in all subjects were obtained retrospectively from medical records. Blood samples in cases and controls were drawn during the hospitalization under standard fasting conditions after a night rest. Lipids and apolipoproteins biomarkers were analyzed enzymatically using automated analyzer systems. All laboratory parameters were routinely analyzed in the hospitalization period in the certified clinical laboratory of the hospital.

Statistical Analyses     

Univariate analyses were conducted to evaluate differences in covariates between matched cases and controls using McNamar’s Chi-Square test for categorical variables. The mean values of the three controls corresponding to each case were taken and paired T-test and Wilcoxon matched pairs signed rank test were performed. Paired t-tests for normally distributed continuous variables and Wilcoxon matched pairs signed rank test for non-normally distributed variables. Spearman correlations between lipid and apolipoproteins were calculated among the controls to determine the relationships and to assess for multi-collinearity. The relationship between lipid and apolipoproteins biomarkers and risk of incident CSDH was examined by using conditional logistic regression to account for the matching to estimate odds ratios (ORs) and 95% confidence intervals for quartiles of lipid biomarkers, with category cut-points defined according to the distribution of the controls with lipid values. Each lipid and apolipoproteins were assessed independently in an adjusted model. Multivariable ORs were estimated from conditional logistic regression models, which accounted for the matching variables, and were additionally adjusted for variables were significant in univariate analyses. Additionally analyses also adjusted for all covariates of interest. Adjusted models were based on case control pairs for whom complete data were available on all covariates of interest. P-values below 0.05 were considered statistically significant. STATA/MP 16.0 was used for all analyses (Stata Corp LP, College Station TX).

Result

Baseline characteristics of the 137 matched pairs that were used in this analysis are shown in Table 1. The proportion of males (75.9%) was much higher than that of females. Compared with controls, cases more likely to have head trauma, hypertensive. No significant difference was noted in diabetes, dementia, malignancy, kidney failure, smoking, anticoagulant use, alcohol use and marital status. As expected, among the controls, the lipid and lipoprotein parameters were highly intercorrelated (Table 2).


 
Table 1

Baseline characteristics of CSDH cases and matched control subjects

 

control(n = 411)

case(n = 137)

p

Male

75.9

75.9

 

Age(95%CI)

72(66, 82)

72(65, 82)

 

Head trauma

   

< 0.001

Yes

46.5

65.0

 

No

53.5

35.0

 

Hypertension

   

< 0.05

Yes

65.2

75.9

 

No

34.8

24.1

 

Diabetes mellitus

   

NS

Yes

86.4

85.4

 

No

13.6

14.6

 

Anticoagulant

   

NS

Yes

98.3

95.6

 

No

1.7

4.4

 

Malignancy

   

NS

Yes

94.4

93.4

 

No

5.6

6.6

 

Dementia

   

NS

Yes

99.0

97.0

 

No

1.0

3.0

 

Kidney failure

     

Yes

0.5

2.1

NS

No

99.5

97.8

 

Smoking

   

NS

Never

62.5

65.7

 

Former

12.2

5.8

 

Current

25.3

28.5

 

Drinking

   

NS

Never

76.9

73.0

 

Former

5.4

4.4

 

Occasion

5.4

6.6

 

Current

12.4

16.1

 

Marital status

   

NS

Marriage

18.0

23.4

 

Single

82.0

76.6

 
Values are given as median (interquartile range) or percentage
CSDH: chronic subdural hematoma


 
Table 2

Spearman correlation coefficients between measured variables among controls

 

Triglyceride

Total cholesterol

HDL-C

LDL-C

ApoA1

ApoB

Triglyceride

1

0.34*

-0.52*

0.29*

-0.23*

0.44*

Total cholesterol

0.34*

1

0.26*

0.84*

0.39*

0.82*

HDL-C

-0.52*

0.26*

1

0.03

0.84*

-0.06*

LDL-C

0.29*

0.84*

0.03

1

0.09

0.91*

ApoA1

-0.23*

0.39*

0.84*

0.09

1

0.08

ApoB

0.44*

0.82*

-0.06*

0.91*

0.08

1

Head trauma

0.11

0.04

-0.04

0.01

-0.03

0.01

Hypertension

0.03

-0.04

-0.06

-0.00

-0.09

-0.02

* P < 0.01
These p-values have been adjusted for multiple comparisons using Bonferroni correction
HDL-C: High density lipoprotein cholesterol, LDL-C: Low density lipoprotein cholesterol, ApoA1: Apolipoprotein A1, ApoB: Apolipoprotein B

In univariate analyses (Table 3), cases had significantly lower median levels of total cholesterol, HDL-C and ApoA1 than control. Additionally, ApoB were significantly higher among controls compared to cases. Baseline levels of triglycerides was higher and LDL-C was lower among the patients with CSDH than among control subjects, but these differences were not statistically significant. Similar results were demonstrated across quartiles and when comparing the fourth quartile of total cholesterol, HDL-C, ApoA1 to the first quartile in unadjusted analyses. Nevertheless, the fourth quartile of triglycerides were significantly higher among controls compared to cases in unadjusted analyses (Table 4). They were significant when comparing the highest quartile to the lowest quartile for total cholesterol (OR 0.35, 95%CI 0.19–0.63, P < 0,001), triglycerides (OR 1.94, 95%CI 1.04–3.60, p < 0,05), HDL (OR 0.25, 95%CI 0.12–0.49, P < 0,001), ApoA1 (OR 0.27,95%CI 0.14–0.52, P < 0,001) in unadjusted analyses.


 
Table 3

Baseline lipid biomarkers in the study population

 

Total

 
 

Control

Case

P value

Triglycerides (mmol/L)

1.57(0.93, 1.84)

1.62(1.11, 1.86)

0.8

Total cholesterol(mmol/L)

4.59(4.02, 5.22)

4.22(3.55, 4.77)

< 0.001

HDL-C (mmol/L)

1.31(1.04, 1.54)

1.13(0.95, 1.43)

< 0.001

LDL-C (mmol/L)

2.55(2.06, 3.03)

2.41(1.98, 2.86)

0.08

ApoA1 (g/L)

1.21(1.00, 1.36)

1.08(0.95, 1.23)

< 0.001

ApoB (g/L)

0.85(0.70, 0.99)

0.82(0.70, 0.94)

< 0.001

Values are given as median (interquartile range)
CI: Confidence interval, HDL-C: High density lipoprotein cholesterol, LDL-C: Low density lipoprotein cholesterol, ApoA1: Apolipoprotein A1, ApoB: Apolipoprotein B


 
Table 4

Unadjusted and adjusted odds of developing CSDH according to quartile of lipid biomarkers at baseline

Variable

 

Odds Ratio (95% Confidence interval)

 
   

1

2

3

4

P for trend

Triglycerides

 
 

Model1

1

1.87(1.00, 3.48)

2.57(1.40, 4.72)

1.94(1.04, 3.60)

0.04

 

Model2

1

1.92(1.01, 3.66)

2.64(1.42, 4.93)

1.98(1.05, 3.71)

0.03

 

Model3

1

2.13(1.10, 4.14)

3.06(1.58, 5.93)

2.06(1.07, 3.96)

0.03

Total cholesterol

 
 

Model1

1

0.64(0.38, 1.09)

0.54(0.32, 0.92)

0.35(0.19, 0.63)

< 0.001

 

Model2

1

0.75(0.43, 1.29)

0.60(0.35, 1.04)

0.34(0.19, 0.64)

< 0.001

 

Model3

1

0.71(0.40, 1.24)

0.55(0.32, 0.96)

0.29(0.15, 0.55)

< 0.001

HDL-C

 
 

Model1

1

0.87(0.53, 1.45)

0.61(0.37, 1.02)

0.25(0.12, 0.49)

< 0.001

 

Model2

1

0.81(0.48, 1.38)

0.59(0.35, 1.00)

0.26(0.13, 0.52)

< 0.001

 

Model3

1

0.77(0.45, 1.32)

0.57(0.33, 0.97)

0.25(0.12, 0.51)

< 0.001

LDL-C

 
 

Model1

1

0.82(0.49, 1.36)

0.76(0.45, 1.27)

0.57(0.33, 1.00)

0.05

 

Model2

1

0.85(0.50, 1.46)

0.79(0.46, 1.34)

0.61(0.35, 1.09)

0.09

 

Model3

1

0.75(0.43, 1.32)

0.77(0.44, 1.33)

0.54(0.30, 0.98)

0.06

ApoA1

 
 

Model1

1

0.8(0.48, 1.32)

0.6(0.36, 1.01)

0.27(0.14, 0.52)

< 0.001

 

Model2

1

0.80(0.48, 1.35)

0.64(0.38, 1.09)

0.27(0.14, 0.52)

< 0.001

 

Model3

1

0.84(0.50, 1.44)

0.62(0.36, 1.07)

0.25(0.12, 0.50)

< 0.001

ApoB

 
 

Model1

1

1.31(0.77, 2.22)

0.89(0.52, 1.52)

0.78(0.45, 1.37)

0.25

 

Model2

1

1.42(0.81, 2.49)

0.91(0.52, 1.58)

0.74(0.42, 1.33)

0.2

 

Model3

1

1.34(0.75, 2.37)

0.89(0.50, 1.57)

0.68(0.37, 1.23)

0.14

Model1 conditioned on age and gender
Model2 conditioned on age and gender, and additionally adjusted for head trauma and hypertensive
Model3 conditioned on model2, and additionally adjusted for diabetes mellitus, dementia, malignancy, kidney failure, anticoagulant use, smoking, alcohol use and marital status
Each row is a separate model with CSDH as the outcome which included quartiles of that specific biomarker
Biomarker quartile cut-points were based on all available controls
HDL-C: High density lipoprotein cholesterol, LDL-C: Low density lipoprotein cholesterol, ApoA1: Apolipoprotein A1, ApoB: Apolipoprotein B

In a multivariable model conditioned on age and gender, and additionally adjusted for head trauma and hypertensive, the ORs of CSDH associated with each biomarker quartile are shown in Table 4. Patients in the highest quartile of triglycerides had a 98% increase in the odds of CSDH versus those in the lowest quartile. Meanwhile, the odds of total cholesterol, HDL and ApoA1 decreased by 66%, 74% and 73%, respectively. Comparing the 4th quartile to the 1st quartile was significant for total cholesterol (OR 0.34, 05%CI 0.19–0.64, P < 0,001), triglycerides (OR 1.98, 95%CI 1.05–3.71, p < 0,05), HDL-C (OR 0.26, 95%CI 0.13–0.52, P < 0,001), ApoA1 (OR 0.27, 95%CI 0.14–0.52, P < 0,001). Another lipid biomarkers at baseline including LDL-C and ApoB were not significantly associated with CSDH. Additional adjustment for diabetes mellitus, dementia, malignancy, kidney failure, anticoagulant use, smoking, alcohol use and marital status did not substantially change the multivariable associations presented in Table 4.

Discussion

In this retrospective evaluation of lipid and apolipoproteins biomarkers associated with CSDH, many biomarkers at baseline -including triglyceride, total cholesterol, HDL-C and ApoA1 were associated with CSDH. Interestingly, our study indicated that individuals with higher total cholesterol levels may decrease the risk of CSDH. Besides, LDL-C and ApoA1 levels at baseline were not associated with CSDH. To the best of our knowledge, this is the first study to directly address the lipid biomarkers associated with the development of CSDH.

In the previous years, many studies have demonstrated that atorvastatin may be an effective nonoperative treatment for CSDH[12-16]. A randomized clinical trial had suggested that atorvastatin could reduce the hematoma volume and improve patients’ neurological function[12]. Atorvastatin is a synthetic competitive inhibitor of 3-hydroxy3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which often be used to decrease the amounts of fatty substances such as total cholesterol, LDL-C and triglycerides in the blood and to increase the amount of HDL-C in the blood[17]. Human ApoA1 circulates in plasma primarily as a component of HDL-C[21]. A survival analysis suggested that low level of HDL is significantly associated with recurrence of CSDH[18]. In the present study, we show for the first time that there is a significant association between lipid and apolipoproteins and risk of CSDH. Our evidence indicates that high level of triglyceride, low level of HDL-C and ApoA1 are significantly associated with CSDH. These finding lend support to the hypothesis that atorvastatin treatment of CSDH may be related to the regulation of lipid and lipoprotein levels in blood. 

However, contrary to our hypothesis, our result found that cases had significantly lower median levels of total cholesterol than control. In a multivariable model we found that the odds of total cholesterol decreased when comparing the 4th quartile to the 1st quartile. Same results were found in the study between cholesterol levels and intracerebral hemorrhage. Several studies have detected that there was a significant inverse association between serum cholesterol level and risk of intracerebral hemorrhage[22-24]. Since few studies have explored the correlation between total cholesterol and CSDH, we don’t know for sure what mechanism causes this inverse correlation. Our results speculate that the mainly mechanism of atorvastatin improve CSDH maybe due to its effect of regulation of angiogenesis and inflammation[25]. Further study should be needed to definitely determine the mechanism why individuals with higher total cholesterol levels have a decreased risk of CSDH. 
    Some limitations of our study should be considered. First, head trauma is a significant risk factor for chronic subdural hematoma, but we do not have enough controls to match every head trauma case with a head trauma control group. Therefor we were only able to select cases of head trauma for a possible match with a control group with head trauma. This inevitably increases selection bias while reducing confounding bias. Second, this is a single-center retrospective study, only 137 patients participated in the case group, and the rigorous conclusion needs to be verified by further large-sample studies.

Conclusion

To our knowledge, this is the first study to assess and demonstrate a relation between serum lipids and apolipoproteins level and chronic subdural hematoma. Our finding indicated that among a panel of lipids and apolipoproteins biomarkers, total cholesterol, triglycerides, HDL-C, ApoA1 were significantly associated with CSDH.

Abbreviations

CSDH: chronic subdural hematoma, CI: Confidence interval, HDL-C: High density lipoprotein cholesterol, LDL-C: Low density lipoprotein cholesterol, ApoA1: Apolipoprotein A1, ApoB: Apolipoprotein B, HMG-CoA: 3-hydroxy3-methylglutaryl-coenzyme A

Declarations

Ethics approval and consent to participate 

The study was reviewed and approved by the first Affiliated Hospital of Chongqing Medical University.

Consent for publication 

Not applicable.

Competing interests 

The authors declare that they have no competing interests.

Availability of data and materials 

The authors declare that the data supporting the findings of this study are available within the article.

Funding

This study was supported by a grant from the National Natural Science Foundation of China (NSFC 81870927).

Acknowledgements 

The authors thank all subjects for participating in this study. The funding source had no role in the study design, collection, analysis and interpretation of the data, in the writing of the report or in the decision to submit the paper for publication.

Authors’ contributions 

Zhaohui He conceived and designed this research. Xudong Che and Wenqiao Fu were responsible for analyzing the data, organizing the manuscript and literature review in the introduction and discussion; Xiaolin Yang and Tangmin Wen were responsible for interpreting the results. Haibo Long and Jun Su was responsible for drafting the introduction and conclusions, in addition to finalizing the writing. The author(s) read and approved the final manuscript.

Author details

Department of Neurosurgery, the first Affiliated Hospital of Chongqing Medical University, Chong Qing, China, 400000

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