|Year : 2012 | Volume
| Issue : 1 | Page : 19-22
Low cholesterol as a risk factor for primary intracerebral hemorrhage: A case-control study
Ashraf V Valappil1, Nilesh V Chaudhary2, R Praveenkumar1, Biju Gopalakrishnan1, AS Girija1
1 Department of Neurology, Malabar Institute of Medical Sciences, Calicut, Kerala, India
2 Department of Medicine, Malabar Institute of Medical Sciences, Calicut, Kerala, India
|Date of Submission||11-Aug-2011|
|Date of Decision||13-Nov-2011|
|Date of Acceptance||24-Nov-2011|
|Date of Web Publication||29-Feb-2012|
Ashraf V Valappil
Department of Neurology, Malabar Institute of Medical Sciences, Govindapuram PO, Calicut - 673 016, Kerala
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: An inverse association between serum cholesterol and the risk of hemorrhagic stroke has been noted in epidemiological studies. We performed a case-control study to assess the relationship between primary intracerebral hemorrhage (ICH) and low serum cholesterol. Materials and Methods: Prospectively recruited fully evaluated patients with ICH were compared with a control group based in a primary care practice, i.e. age- and sex-matched individuals attending the routine preventive health check-up. Low cholesterol was defined by the sex-specific lowest quintile of the population. Results: The proportion of ICH patients with low cholesterol was significantly higher than the controls (68% vs. 43%). Mean total cholesterol was also signficantly low in ICH patients compared with controls (177 mg/dL vs. 200 mg/dl; P-value = 0.0006). Low-density lipoprotein cholesterol (LDL-c) and triglycerides were also significantly low in ICH patients compared with controls. Mean LDL-C in the ICH patient group was 114 mg/dL, whereas it was 128.5 mg/dL in the control group (P-value = 0.016). There was no significant difference in the high-density lipoprotein (HDL) levels in both groups. In a subgroup analysis, both men and women in the ICH group had a significantly low mean cholesterol compared with the control group. Although lower mean cholesterol was seen in both young and older individuals in the ICH group than in controls, the difference was significant only in the older group (age >45 years). In multivariate analysis, presence of low cholesterol remained a significant predictor of hemorrhage. The odds ratio of low cholesterol in the hemorrhage cases was 2.75 (95% CI = 1.44-5.49) unadjusted and 2.15 (1.13-4.70) adjusted for age and hypertension. Conclusions: This study confirms an increased risk of primary ICH associated with low cholesterol both in men and women, especially in older individuals.
Keywords: Case-control study, intracerebral hemorrhage, low cholesterol, risk factor
|How to cite this article:|
Valappil AV, Chaudhary NV, Praveenkumar R, Gopalakrishnan B, Girija A S. Low cholesterol as a risk factor for primary intracerebral hemorrhage: A case-control study. Ann Indian Acad Neurol 2012;15:19-22
|How to cite this URL:|
Valappil AV, Chaudhary NV, Praveenkumar R, Gopalakrishnan B, Girija A S. Low cholesterol as a risk factor for primary intracerebral hemorrhage: A case-control study. Ann Indian Acad Neurol [serial online] 2012 [cited 2021 Nov 30];15:19-22. Available from: https://www.annalsofian.org/text.asp?2012/15/1/19/93270
| Introduction|| |
The paradox of a high stroke incidence in populations with low serum cholesterol has been reported in population-based studies.  One likely explanation for this observation is an inverse relationship between hemorrhagic stroke and serum cholesterol. , In Asian societies, where plasma cholesterol levels are low, hemorrhagic stroke may form up to 30% of all strokes.  Although other factors probably also contribute to this high frequency of intracerebral hemorrhage (ICH), low cholesterol levels have been proposed as one explanation for the high incidence of ICH in these countries. In a population-based study from North-East India, hemorrhagic stroke was found in 32% of the cases.  Three major American studies have confirmed this association. The multiple Risk factor Intervention Trial (MRFIT)  and Honolulu Heart Study (HHS)  analyzed populations of middle-aged men (aged 35-68 years), while the Kaiser programme cohort  consisted of both men and women across a wider range of ages (40-89 years). Other cohorts in Scandinavian and American populations demonstrated an association of low cholesterol with ICH in both sexes over a wider range of ages. ,,, Since the introduction of highly effective means of lowering serum cholesterol by use of statins, the potential importance of this relationship has increased. In order to define the relationship between primary ICH and low cholesterol, we prospectively recruited patients hospitalized with ICH in a case-control design.
| Materials and Methods|| |
Eighty-five consecutive patients admitted to the Malabar Institute of Medical Sciences (MIMS) hospital with a diagnosis of primary ICH were screened for this study between January 2007 and June 2008. Primary ICH was defined as sudden onset of an acute neurological event with confirmation of acute intraparenchymal ICH provided by computed tomography (CT) scanning or magnetic resonance imaging (MRI). CT and MRI findings were clearly distinguished from hemorrhagic transformation based on standard criteria. After initial review for exclusion criteria, 74 patients were enrolled. Patients were excluded because of secondary causes of hemorrhage such as antecedent trauma (3), central nervous system tumor (3), vascular malformation (2), excessive anticoagulation or coagulopathy (3). Each patient was evaluated with history and physical examination by a neurological inpatient service, routine laboratory testing and brain imaging.
The control group consisted of 74 individuals, age- and sex-matched to the patient group presenting to MIMS primary care clinic for routine health checkup during the same study period.
For ICH cases and controls, total cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides were measured in serum by standard chemical methods and low-density lipoprotein cholesterol (LDL-c) calculated by the Friedwald formula. All lipid values are reported in mg/dL. All blood samples were obtained in fasting state within 48 h of admission.
The primary outcome measure established prior to the study and in keeping with the reported epidemiologic data was the proportion of cases and controls with total cholesterol below a threshold level. The low-cholesterol threshold was designated as sex-specific lowest population quintile, <189 mg/dL for men and <202 mg/dL for women.  The proportion of individuals with low cholesterol among hemorrhage cases and control group were compared using 2x2 tables with Fisher's exact test for significance. Mean cholesterol values for cases and controls was calculated and compared using unmatched t-tests. All significance tests were two-sided, with P <0.05 designated as significant unless otherwise stated. All confidence intervals (CI) were set at 95%. Multivariate logistic regression analysis was performed. Potential covariates examined were age (in 5-year intervals) and presence or absence of hypertension. All analysis was performed with SPSS software.
| Results|| |
Of the 74 patients, 50 were males and 24 were females. Mean age was 59.7 ± 14 years. Twelve patients were below 45 years of age. Controls were matched individually by age (+1) and sex. Baseline characteristics of the patient group are shown in [Table 1].
Fifteen patients (21%) in the ICH group were alcoholic and 26 patients (36%) were smokers. Five patients (7%) were taking statins.
CT scan brain was performed in all patients. Thirty-six patients (49%) had a bleed in the basal ganglia and thalamic region, six had cerebellar hemorrhage, two had bleed involving only brainstem, 14 patients had a basal ganglia bleed with significant lobar component and 16 patients had a lobar hemorrhage.
A significantly increased proportion (68%) of hemorrhage cases had total cholesterol values in the sex-specific lowest population quintile. Lower cholesterol values (below 160 mg%) were found in 43% of the patients in the hemorrhage group and 10.2% of the control group (P-value = 0.000). Mean total cholesterol for the ICH patients were significantly low compared with the control group (177 mg/dL vs. 200 mg/dL; P-value = 0.0006). Mean LDL-c and triglycerides were also significantly low in the ICH group [Table 2]. In the subgroup analysis, both men and women in the ICH group had significantly low mean cholesterol compared with the control group. In a separate analysis of patient subgroups based on age, although lower mean cholesterol values were noted in patients less than 45 years of age in the ICH group, the difference was not significant compared with the control group. In ICH patients above 45 years of age, significantly low cholesterol was noted compared with the control group (178 mg/dL vs. 201 mg/dL; P-value = 0.003). There was no significant difference for HDL in mean analysis between cases and controls.
Multivariate analysis was performed to control for potential covariates of cholesterol such as age and hypertension. The presence of low cholesterol remained a significant predictor of hemorrhage. The odds ratio of low cholesterol in the hemorrhage cases was 2.75 (95% CI = 1.44-5.49) unadjusted and 2.15 (1.13-4.70) adjusting for age and hypertension.
Twenty-six patients (35%) died during the hospital stay, 44 patients showed improvement and three patients worsened and was transferred to another center.
| Discussion|| |
Many facts prompted us to analyze relationship between lipids and ICH. An increased relative risk for ICH was observed in women with decreasing serum cholesterol levels, whereas in men, the risk function was U-shaped.  Low levels increased the odds for ICH 2.25-fold after the adjustment for age and apolipoprotein E (APOE) genotype.  This confirmed an increased risk of primary ICH associated with low cholesterol, specifically for hemorrhage due to hypertensive vasculopathy. Low serum cholesterol has been reported as an independent predictor for ICH in men,  elderly men  and men with serum cholesterol in the lowest quintile. 
Our data in patients with well-characterized primary ICH confirm the population-based observation that individuals with lowest cholesterol levels are at an increased risk of ICH. We found ICH to be associated with a significant overrepresentation below a threshold lipid concentration relative to the control group. We also observed a significantly lower mean cholesterol level in patients with ICH compared with the control group. Difference in mean cholesterol was significant in both men and women in our study. Although mean cholesterol was significantly low in both young and elderly individuals, the difference was statistically significant in individuals above 45 years of age. In the largest population-based study MRFIT, the mean cholesterol level in the hemorrhage and nonhemorrhage groups was 211 ± 44 and 214 ± 40, respectively, with a pronounced increase in hemorrhage only among those with cholesterol <160. The HHS and Kaiser cohorts similarly emphasized differences in proportion below a threshold rather than in mean cholesterol levels.
Corroborating previous findings examining ICH and cholesterol, we observed a moderate inverse association between LDL-c and ICH. Triglyceride levels were also inversely associated with ICH. Cholesterol and triglycerides play important roles in the cell membrane. There is increased erythrocyte fragility and decreased platelet aggregability in vitro and in vivo with reduced levels of cholesterol. It has been proposed that lower cholesterol results in a weakened endothelium that more readily leads to arterial fragility, hemorrhages or slower repair after small hemorrhages. , Potentially weakened endothelium may be more susceptible to microaneurysms, the chief pathological finding of cerebral hemorrhages. It remains unclear whether low cholesterol directly promotes ICH by these or other mechanisms. It is perhaps equally likely that the relationship might be based on a common underlying factor rather than a direct causal link.
A different impact of cholesterol, according to the stroke subtype, has also been described with an association between low serum cholesterol and the risk of ICH. A neuroradiological study demonstrated that the multifocal signal loss lesions on T2-weighted gradient echo MRI, which are microbleeds, are histopathologically related to mean concentrations of total cholesterol and LDL-c. Cholesterol and lipid levels were lower in patients with a severe degree of multifocal signal loss lesions on T2-weighted gradient echo MRI than that in those without these lesions. This suggests that lipid profile levels associated with the severity of hypertension may be linked with cerebral microbleeds.
Another fact is the relationship reported in some community-based studies between low cholesterol levels and mortality due to ICH. Low serum cholesterol correlated with risk of death from ICH. , A systematic review of mortality from causes other than ischemic heart disease found that very low serum cholesterol concentration increased mortality from hemorrhagic stroke. 
A potential source of error in this study is the use of lipid values during the first 48 h after ICH. Cholesterol determinations within the first 48 h after MI are thought to be reliable.  Some studies carried out following stroke have shown cholesterol levels to decline in the first 24-48 h after stroke, with a nadir at 1-2 weeks and a return to baseline at 2-3 months.  The fall in cholesterol <48 h after ICH appears to occur somewhat earlier than in myocardial infarction or ischemic stroke. , The cause of the posthemorrhage drop in cholesterol has been attributed to a nonspecific increase in chatecholamines.
Further understanding of the relationship between serum lipids and primary ICH has implications for both prevention of ICH and the potential risks of lipid-lowering therapies. While aggressive programs to lower lipids are of proven benefit, further understanding of the link between extremely low cholesterol and primary ICH could bear on these strategies in the future.
| Acknowledgments|| |
The authors are grateful to Mr. Abdul Muhees and other staff of the Medical Records Department, MIMS Hospital, for their assistance in recruitment and evaluation of control subjects. They would also like to thank Mr. Mohammed Ashraf of the Statistics Department, KMCT College, Calicut, for his statistical assistance.
| References|| |
|1.||Reed DM. The paradox of high risk of stroke populations with low risk of coronary heart disease. Am J Epidemiol 1990;131:579-88. |
|2.||anaka H, Ueda Y, Hayashi M, Date C, Baba T, Yamashita H, et al. Risk factors for cerebral hemorrhage and cerebral infarctions in a Japanese rural community. Stroke 1982;13:62-73. |
|3.||Shimamoto T, Komachi Y, Inada H, Doi M, Iso H, Sato S, et al. Trends for coronary heart disease and stroke and their risk factors in Japan. Circulation 1989;79:503-15. |
|4.||Hu HH, Sheng WY, Ch FL, Lan CF, Chiang BN. Incidence of stroke in Taiwan. Stroke 1992;23:1237-41. |
|5.||Bannered TK, Mukharjee CS, Sarkhel A. Stroke in the urban population of Calcutta-an epidemiological study. Neuroepidemiology 2001;20:201-7. |
|6.||Iso H, Jacobs DR, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six year mortality from stroke in 350,977 men screened for the Multiple Risk Factor Intervention Trial. N Engl J Med 1989;320:904-10. |
|7.||Yano K, Reed DM, Maclean CJ. Serum cholesterol and hemorrhagic stroke in Honolulu Heart Program. Stroke 1989;20:1460-5. |
|8.||Iribarren C, Jacobs DR, Sadler M, Claxton AJ, Sidney S. Low total serum cholesterol and intracerebral hemorrhagic stroke: Is the association confined to elderly men? Stroke 1996;27:1993-8. |
|9.||Gatchev O, Rastam L, Lindberg G, Eklund GA, Isacsson SO. Subarachnoid hemorrhage, cerebral hemorrhage and serum cholesterol in men and women. Ann Epidemiol 1993;3:403-9. |
|10.||Lindenstrom E, Boysen G, Nyboe J. Influence of total cholesterol, high density lipoprotein cholesterol, and triglycerides on risk of cerebrovascular disease: The Copenhagen City Heart Study. Br Med J 1994;309:11-5. |
|11.||Sturgeon JD, Folsom AR, Longstreth WT Jr, Shahar E, Rosamond WD, Cushman M. Risk factors for Intracerebral Hemorrhage in a pooled prospective study. Stroke 2007;38:2718-25. |
|12.||Arisen MJ, Claus SP, Rinkel GJ, Algra A. Risk factors for intracerebral hemorrhage in general population: A systematic review. Stroke 2003;34:2060-5. |
|13.||Segal AZ, Chiu RI, Eggleston-Sexton PM, Beiser A, Greenberg SM. Low Cholesterol as a Risk factor for Primary Intracerebral Hemorrhage: A Case-Control Study. Neuroepidemiology 1999;18:185-93. |
|14.||Okumura K, Iseki K, Wakugami K, Kimura Y, Muratani H, Ikemiya Y, et al. Low serum cholesterol as a risk factor for hemorrhagic stroke in men: A community based mass screening in Okinawa, Japan. Jpn Circ J 1999;63:53-8. |
|15.||Konishi M, Iso H, Komachi Y, Iida M, Shimamoto T, Jacobs DR Jr, et al. Associations of serum cholesterol, different types of stroke and stenosis distribution of cerebral arteries. The Akita Pathology Study. Stroke 1993;24:954-62. |
|16.||Brukdorfer KR, Demel RA, De Gier J, Van Deenen LL. The effect of partial replacement of membrane cholesterol by other steroids on osmotic fragility and glycerol permeability of erythrocytes. Biochim Biophys Acta 1969;183:334-45. |
|17.||Roquer J, Rodriguez-Campello A, Gomos M, Ois A, Munteis E, Bohn P. Serum lipid levels and in hospital mortality in patients with ICH. Neurology 2005;65:1198-202. |
|18.||Ramírez-Moreno JM, Casado-Naranjo I, Portilla JC, Calle ML, Tena D, Falcón A, et al. Serum cholesterol LDL and 90-day mortality in patients with intracerebral hemorrhage. Stroke 2009;40:1917-20. |
|19.||Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. Br Med J 1994;308:373-9. |
|20.||Ryder RE, Hayes TM, Mulligan IP, Kingswood JC, Williams S, Owens DR. How soon after myocardial infarction should plasma lipid value be assessed? Br Med J (Clin Res Ed) 1984;289:1651-3. |
|21.||Woo J, Lam CW, Kay R, Wong HY, Teoh R, Nicholls MG. et al. Acute and long term changes in serum lipids after acute stroke. Stroke 1990;21:1407-11. |
[Table 1], [Table 2]
|This article has been cited by|
||Genetic determinants of LDL cholesterol and risk of intracerebral haemorrhage
| ||Natalia Szejko, Elayna Kirsch, Guido J. Falcone |
| ||Current Opinion in Lipidology. 2021; 32(4): 244 |
|[Pubmed] | [DOI]|
||Association between Anemia and Stroke in Females: A Nationwide, Population-Based Cohort Study in Taiwan
| ||Yuan Sui, Chien-Tai Hong, Li-Nien Chien, Hung-Yi Liu, Hung-Yi Chiou, Yi-Chen Hsieh |
| ||International Journal of Environmental Research and Public Health. 2020; 17(20): 7440 |
|[Pubmed] | [DOI]|
||Elevated oxidative stress among coronary artery disease patients on statin therapy: A cross sectional study
| ||Sabitha Palazhy,Prakash Kamath,Damodaran M. Vasudevan |
| ||Indian Heart Journal. 2015; 67(3): 227 |
|[Pubmed] | [DOI]|
||Association between statin use and intracerebral hemorrhage: a systematic review and meta-analysis
| ||C. Lei,B. Wu,M. Liu,Y. Chen |
| ||European Journal of Neurology. 2013; : n/a |
|[Pubmed] | [DOI]|
||Low cholesterol as a risk factor for primary intracerebral hemorrhage: A case-control study: A comment on the study
| ||Wu, Y.-C. |
| ||Annals of Indian Academy of Neurology. 2012; 15(3): 230 |