The Truth about Low Cholesterol

Also see:
High Cholesterol and Metabolism
Thyroid Status and Oxidized LDL
Inflammatory TSH
“Normal” TSH: Marker for Increased Risk of Fatal Coronary Heart Disease
Thyroid Status and Cardiovascular Disease
The Cholesterol and Thyroid Connection
High Blood Pressure and Hypothyroidism
A Cure for Heart Disease
Hypothyroidism and A Shift in Death Patterns
Low Blood Cholesterol Compromises Immune Function

Quotes by Ray Peat, PhD:
“The brain is the body’s richest source of cholesterol, which, with adequate thyroid hormone and vitamin A, is converted into the steroid hormones pregnenolone, progesterone, and DHEA, in proportion to the quantity circulating in blood in low-density lipoproteins. The brain is also the richest source of these very water-insoluble (hydrophobic) steroid hormones; it has a concentration about 20 times higher than the serum, for example. The active thyroid hormone is also concentrated many-fold in the brain.

DHEA (dehydroepiandrosterone) is known to be low in people who are susceptible to heart disease or cancer, and all three of these steroids have a broad spectrum of protective actions. Thyroid hormone, vitamin A, and cholesterol, which are used to produce the protective steroids, have been found to have a similarly broad range of protective effects, even when used singly.”

“Large scale human studies have provided overwhelming evidence that whenever drugs, including the unsaturated oils, were used to lower serum cholesterol, mortality increased, from a variety of causes including accidents, but mainly from cancer.”

“It is now widely recognised that the pattern of blood lipids associated with lower incidence of heart disease – higher blood levels of the High Density Lipids (HDL) and lower levels of the Low Density Lipids (LDL) – is associated with a higher cancer risk. It seems that any intervention – not just excess vegetable oil – which lowers the LDL cholesterol will increase the risk of cancer.”

“Cholesterol has a long history as a protectant against many toxins; I think this relates to the fact that people with very low cholesterol have such a high incidence of endotoxin-related symptoms.”

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Lancet. 2001 Aug 4;358(9279):351-5.
Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study.
Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD.
BACKGROUND:
A generally held belief is that cholesterol concentrations should be kept low to lessen the risk of cardiovascular disease. However, studies of the relation between serum cholesterol and all-cause mortality in elderly people have shown contrasting results. To investigate these discrepancies, we did a longitudinal assessment of changes in both lipid and serum cholesterol concentrations over 20 years, and compared them with mortality.
METHODS:
Lipid and serum cholesterol concentrations were measured in 3572 Japanese/American men (aged 71-93 years) as part of the Honolulu Heart Program. We compared changes in these concentrations over 20 years with all-cause mortality using three different Cox proportional hazards models.
FINDINGS:
Mean cholesterol fell significantly with increasing age. Age-adjusted mortality rates were 68.3, 48.9, 41.1, and 43.3 for the first to fourth quartiles of cholesterol concentrations, respectively. Relative risks for mortality were 0.72 (95% CI 0.60-0.87), 0.60 (0.49-0.74), and 0.65 (0.53-0.80), in the second, third, and fourth quartiles, respectively, with quartile 1 as reference. A Cox proportional hazard model assessed changes in cholesterol concentrations between examinations three and four. Only the group with low cholesterol concentration at both examinations had a significant association with mortality (risk ratio 1.64, 95% CI 1.13-2.36).
INTERPRETATION:
We have been unable to explain our results. These data cast doubt on the scientific justification for lowering cholesterol to very low concentrations (<4.65 mmol/L) in elderly people.

BMJ. 1990 Aug 11;301(6747):309-14.
Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials.
Muldoon MF, Manuck SB, Matthews KA.
OBJECTIVE:
To determine the effects of lowering cholesterol concentrations on total and cause specific mortality in randomised primary prevention trials.
DESIGN:
Qualitative (meta-analytic) evaluation of total mortality from coronary heart disease, cancer, and causes not related to illness in six primary prevention trials of cholesterol reduction (mean duration of treatment 4.8 years).
PATIENTS:
24,847 Male participants; mean age 47.5 years.
MAIN OUTCOME MEASURES:
Total and cause specific mortalities.
RESULTS:
Follow up periods totalled 119,000 person years, during which 1147 deaths occurred. Mortality from coronary heart disease tended to be lower in men receiving interventions to reduce cholesterol concentrations compared with mortality in control subjects (p = 0.06), although total mortality was not affected by treatment. No consistent relation was found between reduction of cholesterol concentrations and mortality from cancer, but there was a significant increase in deaths not related to illness (deaths from accidents, suicide, or violence) in groups receiving treatment to lower cholesterol concentrations relative to controls (p = 0.004). When drug trials were analysed separately the treatment was found to reduce mortality from coronary heart disease significantly (p = 0.04).
CONCLUSIONS:
The association between reduction of cholesterol concentrations and deaths not related to illness warrants further investigation. Additionally, the failure of cholesterol lowering to affect overall survival justifies a more cautious appraisal of the probable benefits of reducing cholesterol concentrations in the general population.

Epidemiology. 1997 Mar;8(2):137-43.
Decline in serum total cholesterol and the risk of death from cancer.
Zureik M, Courbon D, Ducimetière P.
We investigated whether decline over time in serum cholesterol was associated with the risk of death from cancer in French men. We studied 6,230 working men, age 43-52 years in 1967-1972, who had at least three annual measurements of serum cholesterol. We estimated individual change over time in serum total cholesterol using within-person linear regression. During an average of 17 years of follow-up after the last examination, 747 subjects died from cancer. The multivariate-adjusted relative risks for subjects in the fourth (highest increase in serum total cholesterol), third, and second quartiles, compared with men in the first quartile (who had a decrease in serum total cholesterol), were 0.70 [95% confidence interval (CI) = 0.56-0.87], 0.71 (95% CI = 0.57-0.88), and 0.74 (95% CI = 0.61-0.91), respectively. The group with the highest decline in cholesterol displayed an excess risk for most cancer sites. These associations were more pronounced in subjects whose weight remained stable or decreased over time than in those who gained weight.

The Lancet, Volume 315, Issue 8167, Pages 523 – 526, 8 March 1980
PLASMA LIPIDS AND MORTALITY: A SOURCE OF ERROR
Geoffrey Rose , M.J Shipley
Cause-specific mortality-rates were calculated in 17 718 men aged 40-64 years who participated in the Whitehall Study. Over a 7 1/2 year follow-up, total mortality showed a J-shaped relation to the plasma cholesterol concentration measured at entry to study. This shape resulted from a strong positive relation of plasma cholesterol with deaths from coronary heart-disease (CHD) combined with an opposite (inverse) relation between plasma cholesterol and deaths from other causes. Cancer mortality was 66% higher in the group with the lowest plasma cholesterol than in the group with the highest plasma cholesterol. Further analysis showed that this inverse association between plasma cholesterol and non-CHD deaths was confined to the first 2 years of follow-up; beyond this time total mortality and cholesterol level were evenly and positively correlated. Analysis of data from the Framingham study revealed the same phenomenon, which is presumed to result from the metabolic consequences of cancer which was present but unsuspected at the time of examination.

BMJ. 1996 Sep 14;313(7058):649-51.
Serum cholesterol concentration and death from suicide in men: Paris prospective study I.
Zureik M, Courbon D, Ducimetière P.
OBJECTIVE:
To investigate whether low serum cholesterol concentration or changing serum cholesterol concentration is associated with risk of suicide in men.
DESIGN:
Cohort study with annual repeat measurements of serum cholesterol concentration (for up to four years).
SETTING:
Paris, France.
SUBJECTS:
6393 working men, aged 43-52 in 1967-72, who had at least three measurements of serum cholesterol concentration.
MAIN OUTCOME MEASURES:
Individual change over time in serum cholesterol concentration (estimated using within person linear regression method); death from suicide during average of 17 years’ follow up after last examination.
RESULTS:
32 men committed suicide during follow up. After adjustment for age and other factors, relative risk of suicide for men with low average serum cholesterol concentration (< 4.78 mmol/l) compared with those with average serum cholesterol concentration of 4.78-6.21 mmol/l was 3.16 (95% confidence interval 1.38 to 7.22, P = 0.007). Men whose serum cholesterol concentration decreased by more than 0.13 mmol/l a year had multivariate adjusted relative risk of 2.17 (0.97 to 4.84, P = 0.056) compared with those whose cholesterol remained stable (change of < or = 0.13 mmol/l a year).
CONCLUSION:
Both low serum cholesterol concentration and declining cholesterol concentration were associated with increased risk of death from suicide in men. Although there is some evidence in favour of a concomitant rather than a causal effect for interpreting these associations, long term surveillance of subjects included in trials of lipid lowering treatments seems warranted.

J Womens Health (Larchmt). 2004 Jan-Feb;13(1):41-53.
Why Eve is not Adam: prospective follow-up in 149650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality.
Ulmer H, Kelleher C, Diem G, Concin H.
PURPOSE:
To assess the impact of sex-specific patterns in cholesterol levels on all-cause and cardiovascular mortality in the Vorarlberg Health Monitoring and Promotion Programme (VHM&PP).
METHODS:
In this study, 67413 men and 82237 women (aged 20-95 years) underwent 454448 standardized examinations, which included measures of blood pressure, height, weight, and fasting samples for cholesterol, triglycerides, gamma-glutamyl transferase (GGT), and glucose in the 15-year period 1985-1999. Relations between these variables and risk of death were analyzed using two approaches of multivariate analyses (Cox proportional hazard and GEE models).
RESULTS:
Patterns of cholesterol levels showed marked differences between men and women in relation to age and cause of death. The role of high cholesterol in predicting death from coronary heart disease could be confirmed in men of all ages and in women under the age of 50. In men, across the entire age range, although of borderline significance under the age of 50, and in women from the age of 50 onward only, low cholesterol was significantly associated with all-cause mortality, showing significant associations with death through cancer, liver diseases, and mental diseases. Triglycerides > 200 mg/dl had an effect in women 65 years and older but not in men.
CONCLUSIONS:
This large-scale population-based study clearly demonstrates the contrasting patterns of cholesterol level in relation to risk, particularly among those less well studied previously, that is, women of all ages and younger people of both sexes. For the first time, we demonstrate that the low cholesterol effect occurs even among younger respondents, contradicting the previous assessments among cohorts of older people that this is a proxy or marker for frailty occurring with age.

Circulation. 1995 Nov 1;92(9):2396-403.
Low serum cholesterol and mortality. Which is the cause and which is the effect?
Iribarren C, Reed DM, Chen R, Yano K, Dwyer JH.
BACKGROUND:
Many studies have reported an association between a low or lowered blood total cholesterol (TC) level and subsequent nonatherosclerotic disease incidence or death. The question of whether low TC is a true risk factor or alternatively a consequence of occult disease at the time of TC measurement remains unsettled. To shed new light onto this problem, we analyzed TC change over a 6- year period (from exam 1 in 1965 through 1968 to exam 3 in 1971 through 1974) in relation to subsequent 16-year mortality in a cohort of Japanese American men.
METHODS AND RESULTS:
The study was based on 5941 men 45 to 68 years of age without prior history of coronary heart disease, stroke, cancer, or gastrointestinal-liver disease at exam 1 who also participated in exam 3 of the Honolulu Heart Program. The association of TC change with mortality end points was investigated with two different approaches (continuous and categorical TC change) with standard survival analysis techniques. Falling TC level was accompanied by a subsequent increased risk of death caused by some cancers (hemopoietic, esophageal, and prostate), noncardiovascular noncancer causes (particularly liver disease), and all causes. The risk-factor-adjusted rate of all-cause mortality was 30% higher (relative risk, 1.30; 95% CI, 1.06 to 1.59) among persons with a decline from middle (180 to 239 mg/dL) to low (< 180 mg/dL) TC than in persons remaining at a stable middle level. By contrast, there was no significant increase in all-cause mortality risk among cohort men with stable low TC levels. Nonillness mortality (deaths caused by trauma and suicide) was not related to either TC change or the average of TC levels in exams 1 and 3.
CONCLUSIONS:
These results add strength to the reverse-causality proposition that catabolic diseases cause TC to decrease.

JAMA. 1995 Jun 28;273(24):1926-32.
Serum total cholesterol and mortality. Confounding factors and risk modification in Japanese-American men.
Iribarren C, Reed DM, Burchfiel CM, Dwyer JH.
OBJECTIVE:
To further investigate the relationship between serum total cholesterol (TC) level and mortality due to major causes. In particular, is the elevated mortality among persons with low TC levels due to confounding conditions that both lower TC level and increase the risk of mortality, and is the association between low or high TC level and mortality homogeneous in the population or, alternatively, restricted to persons with other risk factors?
STUDY DESIGN:
Prospective cohort study.
SETTING:
Free-living population in Oahu, Hawaii.
PARTICIPANTS:
A total of 7049 middle-aged men of Japanese ancestry.
MAIN OUTCOME MEASURES:
Age- and risk factor-adjusted mortality due to coronary heart disease, hemorrhagic stroke, cancer, chronic obstructive pulmonary disease, nonmalignant liver disease, trauma, miscellaneous and unknown, and all causes.
RESULTS:
During 23 years of follow-up, a total of 1954 deaths were documented (38% cancer, 25% cardiovascular, and 37% other). Men with low serum TC levels (< 4.66 mmol/L [< 180 mg/dL]) were found to have several adverse health characteristics, including a higher prevalence of current smoking, heavy drinking, and certain gastrointestinal conditions. In an age-adjusted model, and in relation to the reference group (4.66 to 6.19 mmol/L [180 to 239 mg/dL]), those in the lowest TC group (< 4.66 mmol/L [< 180 mg/dL]) were at significantly higher risk of mortality due to hemorrhagic stroke (relative risk [RR], 2.41; 95% confidence interval [Cl], 1.45 to 4.00), cancer (RR, 1.41; 95% Cl, 1.17 to 1.69), and all causes (RR, 1.23; 95% Cl, 1.09 to 1.38). Adjustment for confounders in multivariate analysis (and exclusion of cases with prevalent disease at baseline and deaths through year 5) did not explain the risk of fatal hemorrhagic stroke but reduced the excess risk of cancer mortality by 51% (to 1.20 from 1.41) and reduced the excess risk of all-cause mortality by 56% (to 1.10 from 1.32) in the low TC group. In addition, there were clear differences in the patterns of risk when comparing men with and without selected risk factors (ie, smoking, alcohol consumption, and untreated hypertension).
CONCLUSIONS:
We conclude that the excess mortality at low TC levels can be partially explained by confounding with other determinants of death and by preexisting disease at baseline, and TC-mortality associations are not homogeneous in the population. In our study, TC level was not associated with increased cancer or all-cause mortality in the absence of smoking, high alcohol consumption, and hypertension.

BMJ. 1995 Aug 12;311(7002):409-13.
Low serum total cholesterol concentrations and mortality in middle aged British men.
Wannamethee G, Shaper AG, Whincup PH, Walker M.
OBJECTIVE:
To examine the relation between low serum total cholesterol concentrations and causes of mortality.
DESIGN:
Cohort study of men followed up for an average of 14.8 years (range 13.5-16.0 years).
SETTING:
One general practice in each of 24 British towns.
SUBJECTS:
7735 men aged 40-59 at screening selected at random from the 24 general practices.
MAIN OUTCOME MEASURES:
Deaths from all causes, cardiovascular causes, cancer, and non-cardiovascular, non-cancer causes.
RESULTS:
During the mean follow up period of 14.8 years there were 1257 deaths from all causes, 640 cardiovascular deaths, 433 cancer deaths, and 184 deaths from other causes. Low serum cholesterol concentrations (< 4.8 mmol/l), present in 5% (n = 410) of the men, were associated with the highest mortality from all causes, largely due to a significant increase in cancer deaths (age adjusted relative risk 1.6 (95% confidence interval 1.1 to 2.3); < 4.8 v 4.8-5.9 mmol/l) and in other non-cardiovascular deaths (age adjusted relative risk 1.9 (1.1 to 3.1)). Low serum cholesterol concentration was associated with an increased prevalence of several diseases and indicators of ill health and with lifestyle characteristics such as smoking and heavy drinking. After adjustment for these factors in the multivariate analysis the increased risk for cancer was attenuated (relative risk 1.4 (0.9 to 2.0) and the inverse association with other non-cardiovascular, non-cancer causes was no longer significant (relative risk 1.5 (0.9 to 2.6); < 4.8 v 4.8-5.9 mmol/l). The excess risks of cancer and of other non-cardiovascular deaths were most pronounced in the first five years and became attenuated and non-significant with longer follow up. By contrast, the positive association between serum total cholesterol concentration and cardiovascular mortality was seen even after more than 10 years of follow up.
CONCLUSION:
The association between comparatively low serum total cholesterol concentrations and excess mortality seemed to be due to preclinical cancer and other non-cardiovascular diseases. This suggests that public health programmes encouraging lower average concentrations of serum total cholesterol are unlikely to be associated with increased cancer or other non-cardiovascular mortality.

JAMA. 1987;257(16):2176-2180
Cholesterol and Mortality 30 Years of Follow-up From the Framingham Study
Keaven M. Anderson, PhD, William P. Castelli, MD, Daniel Levy, MD
From 1951 to 1955 serum cholesterol levels were measured in 1959 men and 2415 women aged between 31 and 65 years who were free of cardiovascular disease (CVD) and cancer. Under age 50 years, cholesterol levels are directly related with 30-year overall and CVD mortality; overall death increases 5% and CVD death 9% for each 10 mg/dL. After age 50 years there is no increased overall mortality with either high or low serum cholesterol levels. There is a direct association between falling cholesterol levels over the first 14 years and mortality over the following 18 years (11% overall and 14% CVD death rate increase per 1 mg/dL per year drop in cholesterol levels). Under age 50 years these data suggest that having a very low cholesterol level improves longevity. After age 50 years the association of mortality with cholesterol values is confounded by people whose cholesterol levels are falling—perhaps due to diseases predisposing to death.

Br Med J (Clin Res Ed). 1985 February 9; 290(6466): 422–424.
Are low cholesterol values associated with excess mortality?
C E Salmond, R Beaglehole, and I A Prior
The relation between cholesterol concentration and mortality was studied prospectively over 17 years in 630 New Zealand Maoris aged 25-74. The dead or alive state of each person was determined in 1981. The causes of death were divided into three categories: cancer, cardiovascular disease, and “other.” Using univariate and both linear and non-linear multivariate methods of analysis for survivorship data, significant inverse relations with serum cholesterol were found for total mortality in women, for mortality from cancer in men and women, and for other causes of mortality in both men and women. The inverse and non-linear association with total mortality in women remained significant when deaths in the first five years of follow up were excluded. This suggests that the association was not explained by undetected illness causing low cholesterol concentrations at the time of initial examination.

Br Med J. 1980 Feb 2;280(6210):285-7.
Cholesterol and mortality in New Zealand Maoris.
Beaglehole R, Foulkes MA, Prior IA, Eyles EF.
The relation between serum cholesterol concentration and mortality was studied prospectively over 11 years in 630 New Zealand Maoris aged 25-74. Serum cholesterol concentration was measured at initial examination in 1962-3 in 94% of the subjects and whether each was dead or alive was determined in 1974. The causes of death were divided into three categories: cancer, cardiovascular disease, and “other.” The Mantel-Haenszel method of analysis of survivorship data showed a significant inverse relation between serum cholesterol concentration and overall mortality in men (x 2/2 = 11.6; p = 0.003) and women (x 2/2 = 7.6; p = 0.02) with odds ratios of 2.3 and 1.9 respectively. Similar significant inverse relations were found for cancer and “other” causes of death. These relations remained significant when baseline age, systolic blood pressure, and the Quetelt index were controlled in Cox’s proportional hazards regression model. The results of this study provide evidence for a potentially deleterious effect of low serum cholesterol concentration. Hence, further research is needed before indiscriminate efforts are made to lower serum cholesterol concentrations in New Zealand Maoris.

Am J Clin Nutr February 2000 vol. 71 no. 2 569-57
Association of low plasma cholesterol with mortality for cancer at various sites in men: 17-y follow-up of the prospective Basel study
Monika Eichholzer, Hannes B Stähelin, Felix Gutzwiller, Eric Lüdin and Florence Bernasconi
Background: Low serum cholesterol has been associated with an increased risk of cancer mortality in various studies, which has led to uncertainty regarding the benefit of lower blood cholesterol.
Objective: The aim of our study was to evaluate the association between low blood cholesterol (<5.16 mmol/L) and cancer at sites that have rarely been evaluated. We placed special emphasis on the potential confounding effect of antioxidant vitamins.
Design: Plasma concentrations of cholesterol and antioxidant vitamins were measured in 1971–1973 in 2974 men working in Basel, Switzerland. In 1990, the vital status of all participants was assessed.
Results: Two hundred ninety of the participants had died from cancer, 87 from lung, 30 from prostate, 28 from stomach, and 22 from colon cancer. Group means for plasma cholesterol concentrations did not differ significantly between survivors and those who died from cancer at any of the studied sites. With plasma cholesterol, vitamins C and E, retinol, carotene, smoking, and age accounted for in a Cox model, an increase in total cancer mortality in lung, prostate, and colon but not in stomach cancer mortality was observed in men >60 y of age with low plasma cholesterol. When data from the first 2 y of follow-up were excluded from the analysis, the relative risk estimates remained practically unchanged with regard to lung cancer but decreased for colon, prostate, and overall cancer.
Conclusions: Increased cancer mortality risks associated with low plasma cholesterol were not explained by the confounding effect of antioxidant vitamins, but were attributed in part to the effect of preexisting cancer.

J Clin Epidemiol. 1992 Jun;45(6):595-601.
The low cholesterol-mortality association in a national cohort.
Harris T, Feldman JJ, Kleinman JC, Ettinger WH Jr, Makuc DM, Schatzkin AG.
The relationship of low serum cholesterol and mortality was examined in data from the NHANES I Epidemiologic Followup Study (NHEFS) for 10,295 persons aged 35-74, 5833 women with 1281 deaths and 4462 men with 1748 deaths (mean (followup = 14.1 years). Serum cholesterol below 4.1 mmol/l was associated with increased risk of death in comparison with serum cholesterol of 4.1-5.1 mmol/l (relative risk (RR) for women = 1.7, 95% confidence interval (CI) = (1.2, 2.3); for men RR = 1.4, CI = (1.1, 1.7)). However, the low serum cholesterol-mortality relationship was modified by time, age, and among older persons, activity level. The low serum cholesterol-mortality association was strongest in the first 10 years of followup. Moreover, this relationship occurred primarily among older persons (RR for low serum cholesterol for women 35-59 = 1.0 (0.6, 1.8), for women 70-74, RR = 2.1 (1.2, 3.7); RR for low serum cholesterol for men 35-59 = 1.2 (0.8, 2.0), for men 70-74, RR = 1.9 (1.3, 2.7)). Among older persons, however, the low serum cholesterol-mortality association was confined only to those with low activity at baseline. Factors related to underlying health status, rather than a mortality-enhancing effect of low cholesterol, likely accounts for the excess risk of death among persons with low cholesterol. The observed low cholesterol-mortality association therefore should not discourage public health programs directed at lowering serum cholesterol.

J Clin Epidemiol. 1992 Apr;45(4):333-46.
Will lowering population levels of serum cholesterol affect total mortality? Expectations from the Honolulu Heart Program.
Frank JW, Reed DM, Grove JS, Benfante R.
Major campaigns now underway to reduce the serum cholesterol levels of entire national populations have not given serious consideration to the high rates of noncardiovascular disease and death associated with low cholesterol levels (less than 190 mg/dl). To explore this problem, the relationships between serum cholesterol levels, measured in 1965-1968 in 7478 Japanese American men in Hawaii, and subsequent total and cause-specific mortality through 1985, were analyzed by multivariate Cox regression to control for potential confounders. Total mortality rates for 1648 deaths showed a U-shaped curve by baseline cholesterol level, with significant inverse trends (p less than 0.03) for deaths due to hemorrhagic stroke, all cancer, benign liver disease, chronic obstructive lung disease and “unknown cause”. Only the inverse trends for cancer and benign liver disease showed flattening when 227 deaths in the first 5 years of follow-up were deleted from the analysis. Simulation models using three different strategies of cholesterol reduction in this cohort revealed that none of these approaches had any substantial impact on predicted total mortality over 15 years. However, the population-based approach might theoretically increase mortality for 60% of the cohort with baseline cholesterol levels less than 225 mg/dl.

Circulation. 1997;96:1408-1415
Serum Cholesterol and Mortality Rates in a Native American Population With Low Cholesterol Concentrations: A U-Shaped Association
Anne Fagot-Campagna, MD, MPH; Robert L. Hanson, MD, MPH; K. M. Venkat Narayan, MD, MSc; Maurice L. Sievers, MD; David J. Pettitt, MD; Robert G. Nelson, MD, MPH; ; William C. Knowler, MD, DrPH
Background Low serum cholesterol concentrations are associated with high death rates from cancer, trauma, and infectious diseases, but the meaning of these associations remains controversial. The present report evaluates whether low cholesterol is likely to be a causal factor for mortality from all causes or from specific causes.
Methods and Results Among 4553 Pima Indians ≥20 years old, a population with low serum cholesterol (median, 4.50 mmol/L), 1077 deaths occurred during a mean follow-up of 12.8 years. Trauma was the most common cause. The relationship between serum cholesterol measured at 2-year intervals and age- and sex-standardized mortality rates was U-shaped. Cholesterol was related positively to mortality from cardiovascular diseases and diabetes (including nephropathy) and negatively to mortality from cancer and alcohol-related diseases. The relationship was U-shaped for mortality from infectious diseases, and cholesterol was not related to mortality from trauma. Change in cholesterol from one examination to the next was positively related to mortality from diabetes. In proportional-hazards models adjusted for potential confounders, the relationship between baseline cholesterol and mortality was U-shaped for all causes and diabetes and positive for cardiovascular diseases. Other relationships were nonsignificant. Among 3358 subjects followed ≥5 years, the relationship was significant and positive only for mortality from cardiovascular diseases.
Conclusions Despite a high exposure risk for Pima Indians, if low cholesterol level is a causal factor, the relationships between low serum cholesterol and high mortality rates probably result from diseases lowering cholesterol rather than from a low cholesterol causing the diseases.

BMJ. 1995 Jun 24;310(6995):1632-6.
Serum cholesterol concentrations in parasuicide.
Gallerani M, Manfredini R, Caracciolo S, Scapoli C, Molinari S, Fersini C.
OBJECTIVE:
To evaluate whether people who have committed parasuicide have low serum cholesterol concentrations.
DESIGN:
Results of blood tests in subjects admitted to hospital for parasuicide compared with those of a control group of non-suicidal subjects; comparison in subgroup of parasuicide subjects of two sets of blood test results (one set from admission for parasuicide and the other from admission for some other illness).
SETTING:
General hospital, Ferrara, Italy.
SUBJECTS:
331 parasuicide subjects aged 44 (SD 21) years (109 with two sets of blood test results) and 331 controls.
MAIN OUTCOME MEASURES:
Serum cholesterol concentrations and possible association with parasuicide, considering sex, violence of method of parasuicide, and underlying psychiatric disorder.
RESULTS:
Lower serum cholesterol concentrations (4.96 (SD 1.16) mmol/l) were found in the parasuicide subjects than in the controls (5.43 (1.30); P < 0.001), regardless of sex and degree of violence of parasuicide method. Both men and women with two sets of blood test results had lower cholesterol concentrations after parasuicide. Linear regression analysis showed that the difference in cholesterol concentrations was significantly related to the length of time between the taking of the two sets of blood samples.
CONCLUSION:
The study showed low cholesterol concentrations after parasuicide. This finding agrees with previous studies, which suggest an association between low cholesterol concentration and suicide.

Coll Antropol. 2005 Jun;29(1):153-7.
Are there differences in serum cholesterol and cortisol concentrations between violent and non-violent schizophrenic male suicide attempters?
Marcinko D, Martinac M, Karlović D, Filipcić I, Loncar C, Pivac N, Jakovljević M.
Previous studies have shown an association between low concentration of serum cholesterol, as well as high concentration of serum cortisol, in suicide behavior. The aim of this study was to evaluate whether men after a violent suicide attempts have different serum cholesterol and cortisol concentrations than those who attempted suicide by non-violent methods. Venous blood samples were collected within 24 hours of admission, to study concentrations of serum cholesterol and cortisol. The sample consisted of 31 male subjects suffering from schizophrenia, admitted in a general hospital after suicide attempt, and was compared with 15 schizophrenic nonsuicidal male controls. Patients with a violent suicidal attempt were found to have significantly lower cholesterol levels and significantly higher cortisol level than patients with non-violent attempts and the control subjects. Our findings suggest that suicide attempts should not be considered a homogenous group. The hypothesis of an association of violent suicidal attempts and peripheral biological markers (cholesterol and cortisol) was supported by our findings.

Eur Psychiatry. 2003 Feb;18(1):23-7.
Cholesterol concentrations in violent and non-violent women suicide attempters.
Vevera J, Zukov I, Morcinek T, Papezová H.
The aim of this study was to evaluate whether women with a history of violent suicide attempts have lower serum cholesterol concentrations than those who attempted suicide by non-violent methods. Our retrospective study used a case-control design to compare serum total cholesterol concentration, hematocrit, red blood cell count and body mass index (BMI) in women with a history of violent (n = 19) or non-violent (n = 51) suicide attempts and of non-suicidal controls (n = 70) matched by diagnosis and age. Analysis of covariance (ANCOVA) with age as the covariate was used to analyze differences in cholesterol levels in groups according to violence. Violence was found to be a significant factor (P = 0.016). Using the Scheffé test, a significant difference (P = 0.011) was revealed between the group of violent and non-violent suicide attempters and between the violent suicide attempters and the control group. Patients with a violent suicidal attempt have significantly lower cholesterol levels than patients with non-violent attempts and the control subjects. Our findings suggest that suicide attempts should not be considered a homogeneous group. They are consistent with the theory that low levels of cholesterol are associated with increased tendency for impulsive behavior and aggression and contribute to a more violent pattern of suicidal behavior.

Psychiatry Res. 2000 Aug 21;95(2):103-8.
Low serum cholesterol in violent but not in non-violent suicide attempters.
Alvarez JC, Cremniter D, Gluck N, Quintin P, Leboyer M, Berlin I, Therond P, Spreux-Varoquaux O.
Many previous studies have suggested that low or lowered serum cholesterol levels may increase the risk of mortality not due to somatic disease: principally, suicide and violent death. Because violent death is rare, some studies have investigated afterwards the relation between cholesterol levels and either suicide attempts in psychiatric populations or violence in criminally violent populations. However, none of these studies have compared cholesterol levels in violent and non-violent suicide attempters. The blood of 25 consecutive drug-free patients following a violent suicide attempt and of 27 patients following a non-violent suicide attempt by drug overdose was drawn in the 24 h following admission. Patients with a diagnosis of alcohol abuse and with cholesterol-lowering therapy were excluded. Age, sex, body mass index, psychiatric diagnosis and the physical conditions of the suicide attempt were investigated. Thirty-two healthy subjects were used as a control group. There were no differences between the groups in age, frequency of psychiatric diagnoses or body mass index. There was more women in the group of non-violent suicide attempters than in that of violent suicide attempters (P<0.001). In analyses controlling for sex and age, the serum cholesterol concentration was 30% lower (F(2,82)=15.8; P<0.0001) in the group of violent suicide attempters (147+/-54 mg/dl) than in the group of non-violent suicide attempters (209+/-38 mg/dl) or control subjects (213+/-46 mg/dl). Our results showed that low serum cholesterol level is associated with the violence of the suicide attempt and not with the suicide attempt itself. Further investigations are necessary to determine the usefulness of this easily accessible parameter as a potential risk indicator for violent acts such as violent suicidal behavior in susceptible individuals.

Br J Psychiatry. 2000 Jul;177:77-83.
Total serum cholesterol in relation to psychological correlates in parasuicide.
Garland M, Hickey D, Corvin A, Golden J, Fitzpatrick P, Cunningham S, Walsh N.
BACKGROUND:
Low cholesterol may act as a peripheral marker for parasuicide.
AIMS:
To examine the relationship between total serum cholesterol and psychological parameters in parasuicide.
METHOD:
Total serum cholesterol and self-rated scores for impulsivity, depression and suicidal intent were measured in 100 consecutive patients following parasuicide, pair-matched with normal and psychiatric control groups.
RESULTS:
Backward, stepwise multiple regression analysis revealed a significantly lower mean cholesterol in the parasuicide population (P < 0.01). Across all groups there was an independent significant (P < 0.01) negative correlation between cholesterol and self-reported scores of impulsivity. No correlation existed between cholesterol and scores for depression or suicidal intent.
CONCLUSIONS:
The data confirm previous reports of low cholesterol in parasuicide. This is the first reported investigation of the construct of impulsivity in relation to cholesterol. We hypothesise that the reported increased mortality in populations with low cholesterol may derive from increased suicide and accident rates consequent on increased tendencies to impulsivity in these populations.

BMJ. 1994 Feb 5;308(6925):373-9.
Assessing possible hazards of reducing serum cholesterol.
Law MR, Thompson SG, Wald NJ.
Abstract
OBJECTIVE:
To assess whether low serum cholesterol concentration increases mortality from any cause.
DESIGN:
Systematic review of published data on mortality from causes other than ischaemic heart disease derived from the 10 largest cohort studies, two international studies, and 28 randomised trials, supplemented by unpublished data on causes of death obtained when necessary.
MAIN OUTCOME MEASURES:
Excess cause specific mortality associated with low or lowered serum cholesterol concentration.
RESULTS:
The only cause of death attributable to low serum cholesterol concentration was haemorrhagic stroke. The excess risk was associated only with concentrations below about 5 mmol/l (relative risk 1.9, 95% confidence interval 1.4 to 2.5), affecting about 6% of people in Western populations. For noncirculatory causes of death there was a pronounced difference between cohort studies of employed men, likely to be healthy at recruitment, and cohort studies of subjects in community settings, necessarily including some with existing disease. The employed cohorts showed no excess mortality. The community cohorts showed associations between low cholesterol concentration and lung cancer, haemopoietic cancers, suicide, chronic bronchitis, and chronic liver and bowel disease; these were most satisfactorily explained by early disease or by factors that cause the disease lowering serum cholesterol concentration (depression causes suicide and lowers cholesterol concentration, for example). In the randomised trials nine deaths (from a total of 687 deaths not due to ischaemic heart disease in treated subjects) were attributed to known adverse effects of the specific treatments, but otherwise there was no evidence of an increased mortality from any cause arising from reduction in cholesterol concentration.
CONCLUSIONS:
There is no evidence that low or reduced serum cholesterol concentration increases mortality from any cause other than haemorrhagic stroke. This risk affects only those people with a very low concentration and even in these will be outweighed by the benefits from the low risk of ischaemic heart disease.

BMJ. 1992 Aug 1;305(6848):277-9.
Low serum cholesterol concentration and short term mortality from injuries in men and women.
Lindberg G, Råstam L, Gullberg B, Eklund GA.
OBJECTIVE:
To determine whether total serum cholesterol concentration predicts mortality from injuries including suicide.
DESIGN:
Cohort study of men and women who had their serum cholesterol concentration measured as part of a general health survey in Värmland, Sweden in 1964 or 1965 and were followed up for an average of 20.5 years.
SUBJECTS:
Adults participating in health screening in 1964-5 (26,693 men and 27,692 women). The study sample was restricted to subjects aged 45-74 years during any of the 20.5 years of follow-up.
MAIN OUTCOME MEASURES:
Serum cholesterol concentration. Deaths from all injuries and suicides during three periods of follow up (0-6 years, 7-13 years, and 14-21 years) according to the Swedish mortality register in subjects aged 45-74. Adjustment was made for prevalent cancer (identified from the Swedish cancer register) at the time of a suicide.
RESULTS:
A strong negative relation between cholesterol concentration and mortality from injuries was found in men during the first seven years of follow up. The relative risk in the lowest 25% of the cholesterol distribution was 2.8 (95% confidence interval 1.52 to 4.96) compared with the top 25%. Most of the excess risk was caused by suicide with a corresponding relative risk of 4.2 (p for trend = 0.001). Correction for prevalent cancer did not change the results. Events occurring during the latter two thirds of the 20.5 years of follow up were not predicted. In women no relation between cholesterol concentration and mortality from injuries was found.
CONCLUSIONS:
Together with observations from intervention trials the findings support the existence of a relation between serum cholesterol concentration and suicide. The causality of such a relation is, however, not resolved.

Circulation. 1992 Sep;86(3):1026-9.
Health policy on blood cholesterol. Time to change directions.
Hulley SB, Walsh JM, Newman TB.

J Card Fail. 2002 Aug;8(4):216-24.
Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure.
Horwich TB, Hamilton MA, Maclellan WR, Fonarow GC.
BACKGROUND:
Although hypercholesterolemia is a well-defined risk factor for morbidity and mortality in coronary artery disease, the relationship between cholesterol and heart failure (HF) has rarely been investigated.
METHODS:
Cholesterol and lipoproteins were measured in 1,134 patients with advanced HF who presented to a single center for HF management and transplant evaluation. Patients were stratified into five groups based on quintiles of total cholesterol (TC) level, and differences in patient characteristics and survival were evaluated.
RESULTS:
Patients with low TC had significantly lower low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), sodium, albumin, left ventricular ejection fraction, and cardiac output. The TC quintiles were similar in terms of HF etiology, hypertension, diabetes, and lipid-lowering therapy at time of referral. TC, LDL, HDL, and TG each predicted survival (P < or = .01) on univariate analysis, with improved survival at higher levels. After adjustment for risk factors using a Cox proportional hazards model, relative risks were 2.071, 1.369, 1.391, 1.006 for the first, second, third, and fourth TC quintiles, with quintile 5 as reference.
CONCLUSIONS:
Serum TC represents a novel prognostic factor for patients with advanced HF. Further studies are necessary to investigate a potential role of low cholesterol and lipoproteins in the pathophysiology of HF progression.

J Am Coll Cardiol. 2003 Dec 3;42(11):1933-40.
The relationship between cholesterol and survival in patients with chronic heart failure.
Rauchhaus M, Clark AL, Doehner W, Davos C, Bolger A, Sharma R, Coats AJ, Anker SD.
OBJECTIVES:
We sought to describe the relationship between cholesterol and survival in patients with chronic heart failure (CHF).
BACKGROUND:
Increasing lipoprotein levels are a cardiovascular risk factor. In patients with CHF, the prognostic value of endogenous lipoproteins is not fully clarified.
METHODS:
A group of 114 patients with CHF recruited to a metabolic study was followed for a minimum of 12 months (derivation study). The results were applied to a second group of 303 unselected patients with CHF (validation study). The relationship between endogenous lipoproteins and survival was explored.
RESULTS:
In the derivation study, survival at 12 months was 78% (95% confidence interval [CI] 70% to 86%) and 56% (95% CI 51% to 62%) at 36 months. Increasing total serum cholesterol was a predictor of survival (hazard ratio 0.64, 95% CI 0.48 to 0.86), independent of the etiology of CHF, age, left ventricular ejection fraction, and exercise capacity. Receiver-operating characteristic curves demonstrated a best cut-off value of The chance of survival increased 25% for each mmol/l increment in total cholesterol. Survival rates above and below the cut-off value for cholesterol in patients with ischemic heart disease (n = 181) were 92% (95% CI 89 to 94) versus 75% (95% CI 64 to 85%) at one year and 72% (95% CI 67 to 76%) versus 50% (95% CI 43 to 56%) at three years.
CONCLUSIONS:
In patients with CHF, lower serum total cholesterol is independently associated with a worse prognosis.

Critical Care Medicine: April 1996 – Volume 24 – Issue 4 – pp 584-589
Low lipid concentrations in critical illness: Implications for preventing and treating endotoxemia
Gordon, Bruce R. MD; Parker, Thomas S. PhD; Levine, Daniel M. PhD; Saal, Stuart D. MD; Wang, John C. L. MD PhD; Sloan, Betty-Jane MA; Barie, Philip S. MD FCCM; Rubin, Albert L. MD
Objectives: To determine the prevalence and clinical significance of hypolipidemia found in critically ill patients, and whether the addition of a reconstituted lipoprotein preparation could inhibit the generation of tumor necrosis factor-alpha (TNF-alpha) in acute-phase blood taken from these patients.
Setting: Surgical intensive care unit (ICU) of a large urban university hospital.
Design: Prospective case series.
Patients: A total of 32 patients with a variety of critical illnesses had lipid and lipoprotein concentrations determined. Six patients and six age- and gender-matched control subjects had whole blood in vitro studies of the effect of lipoprotein on lipopolysaccharide mediated TNF-alpha production.
Interventions: Blood samples were drawn on admission to the ICU and over a subsequent 8-day period.
Measurements and Main Results: Mean serum lipid and lipoprotein values obtained from patients within 24 hrs of transfer to the surgical ICU were extremely low: mean total cholesterol was 117 mg/dL (3.03 mmol/L), low-density lipoprotein cholesterol 71 mg/dL (1.84 mmol/L), and high-density lipoprotein cholesterol 25 mg/dL (0.65 mmol/L). Only the mean triglyceride concentration of 105 mg/dL (1.19 mmol/L), and the mean lipoprotein(a) concentration of 25 mg/dL (0.25 g/L) were within the normal range. During the first 8 days following surgical ICU admission, there were trends toward increasing lipid and lipoprotein concentrations that were significant for triglycerides and apolipoprotein B. Survival did not correlate with the lipid or lipoprotein concentrations, but patients with infections had significantly lower (p equals .008) high-density lipoprotein cholesterol concentrations compared with noninfected patients. Lipopolysaccharide-stimulated production of TNF-alpha in patient and control blood samples was completely suppressed by the addition of 2 mg/mL of a reconstituted high-density lipoprotein preparation.
Conclusions: Patients who are critically ill from a variety of causes have extremely low cholesterol and lipoprotein concentrations. Correction of the hypolipidemia by a reconstituted high density lipoprotein preparation offers a new strategy for the prevention and treatment of endotoxemia.

Crit Care. 2003; 7(6): 413–414.
Hypocholesterolemia in sepsis and critically ill or injured patients
Robert F Wilson,corresponding author1 Jeffrey F Barletta,2 and James G Tyburski3
Hypocholesterolemia is an important observation following trauma. In a study of critically ill trauma patients, mean cholesterol levels were significantly lower (119 ± 44 mg/dl) than expected values (201 ± 17 mg/dl). In patients who died, final cholesterol levels fell by 33% versus a 28% increase in survivors. Cholesterol levels were also adversely affected by infection or organ system dysfunction. Other studies have illustrated the clinical significance of hypocholesterolemia. Because lipoproteins can bind and neutralize lipopolysaccharide, hypocholesterolemia can negatively impact outcome. New therapies directed at increasing low cholesterol levels may become important options for the treatment of sepsis.

Am J Clin Nutr. 2004 Aug;80(2):291-8.
Serum cholesterol concentrations are associated with visuomotor speed in men: findings from the third National Health and Nutrition Examination Survey, 1988-1994.
Zhang J, Muldoon MF, McKeown RE.
BACKGROUND:
Current international recommendations advise aggressive treatment of relative hypercholesterolemia despite an incomplete understanding of any neurobehavioral effects of low or lowered serum cholesterol.
OBJECTIVE:
The objective was to examine the relation between serum cholesterol concentrations and performance in immediate memory, visuomotor speed, and coding speed tests.
DESIGN:
The participants were 4110 adults aged 20-59 y who completed a set of neurobehavioral tests and had blood specimens collected as a part of the third National Health and Nutrition Examination Survey, 1988-1994.
RESULTS:
After adjustment for sociodemographic variables, serum trace elements and vitamins, dietary energy intake, and risk factors for cardiovascular disease, we found inverse linear associations of serum total cholesterol and non-HDL cholesterol with visuomotor speed in men. The least-squares mean (+/- SE) visuomotor speeds were 231.6 +/- 2.6, 224.0 +/- 2.2, and 218.9 +/- 2.5 ms, respectively, for men with serum total cholesterol concentrations below the 25th, between the 25th and the 75th, and at or above the 75th percentile (P for trend < 0.001) and were 231.7 +/- 2.7, 225.8 +/- 2.4, and 214.1 +/- 2.3 ms, respectively, for men with a non-HDL-cholesterol concentration below the 25th, between the 25th and the 75th, and at or above the 75th percentile (P for trend < 0.001). No significant associations were observed between memory or coding speed and the selected serum cholesterol measures in men, and the scores of the 3 neurobehavioral tests were unrelated to serum cholesterol in women.
CONCLUSION:
Low serum total cholesterol and non-HDL cholesterol are associated with slow visuomotor speed in young and middle-aged men.

Annals of Internal Medicine March 15, 1998 vol. 128 no. 6 478-487
Cholesterol and Violence: Is There a Connection?
Beatrice A. Golomb, MD, PhD
Purpose: To determine whether the seeming relation between low or lowered cholesterol levels and violence is consistent with causality according to Hill’s criteria and whether construct validity is supported by convergence of findings across different types of studies.
Data Sources: Search of the MEDLINE database for English-language articles published between 1965 and 1995 was supplemented by searches of the PsycINFO and Current Contents databases and bibliographies of relevant articles.
Study Selection: Peer-reviewed observational and experimental articles and meta-analyses that presented original research; related cholesterol levels to behaviorally defined violence; and if experimental, had single-factor (lipid-only) intervention.
Data Extraction: Studies were grouped according to type. Data on the relation of violence to cholesterol levels from each study were recorded.
Data Synthesis: Observational studies (including cohort, case–control, and cross-sectional studies) consistently showed increased violent death and violent behaviors in persons with low cholesterol levels. Some meta-analyses of randomized trials found excess violent deaths in men without heart disease who were randomly assigned to receive cholesterol-lowering therapy. Experimental studies showed increased violent behaviors in monkeys assigned to low-cholesterol diets. Human and animal research indicates that low or lowered cholesterol levels may reduce central serotonin activity, which in turn is causally linked to violent behaviors. Many trials support a significant relation between low or lowered cholesterol levels and violence (P < 0.001).
Conclusions: A significant association between low or lowered cholesterol levels and violence is found across many types of studies. Data on this association conform to Hill’s criteria for a causal association. Concerns about increased risk for violent outcomes should figure in risk–benefit analyses for cholesterol screening and treatment.

Pharmacopsychiatry. 1999 Jan;32(1):1-4.
The risk of acute suicidality in psychiatric inpatients increases with low plasma cholesterol.
Papassotiropoulos A, Hawellek B, Frahnert C, Rao GS, Rao ML.
Several studies suggest that the reduction of total cholesterol in blood by lipid-lowering agents is accompanied by a decrease in the incidence of coronary heart disease, but not in total mortality. Likewise, epidemiological studies show that low total cholesterol concentrations appear to be associated with an increased risk of death from suicide and injuries. There is little information with respect to acute suicidality and cholesterol in psychiatric inpatients; therefore the aim of the present study was to examine exactly this relation between plasma cholesterol and acute suicidality. The study comprised 45 acutely suicidal psychiatric inpatients, 95 nonsuicidal inpatients with affective disorder, and 20 healthy subjects. Psychopathological measures (Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, Beck’s Suicide Intent Scale) were established in these patients as well as the plasma concentrations of cholesterol in patients and healthy subjects. The most important finding of this study is that the risk of acute suicidality decreases with increasing total cholesterol levels irrespective of age, gender, and nutritional status (i.e., body mass index). Comparison of total cholesterol levels between age- and sex-matched suicidal and nonsuicidal patients with affective disorder supports this observation: Despite the slightly higher body mass index, suicidal patients have significantly lower cholesterol levels than nonsuicidal patients. Our findings support the notion that acute suicidality is associated with low plasma cholesterol; this observation needs to be further studied in the context of a biological marker for suicide risk.

J Affect Disord. 2001 Feb;62(3):217-9.
Cholesterol and serotonin indices in depressed and suicidal patients.
Sarchiapone M, Camardese G, Roy A, Della Casa S, Satta MA, Gonzalez B, Berman J, De Risio S.
BACKGROUND:
Prolactin and cortisol responses to d-fenfluramine challenge of central serotonin are reduced in depressed and suicidal patients. Low serum cholesterol levels are also reported in suicidal behavior. Thus, we examined for a relationship between serum cholesterol and fenfluramine challenge responses in patients with depression and/or attempted suicide.
METHODS:
We studied 12 patients and six controls. Blood was drawn for baseline serum cholesterol and the d-fenfluramine challenge test performed.
RESULTS:
Serum cholesterol levels were significantly lower in suicidal patients than in either non-suicidal patients or controls. However, neither the prolactin nor cortisol responses to d-fenfluramine correlated significantly with serum cholesterol levels.
CONCLUSION:
No relationship was found between serum cholesterol and these peripheral indices of serotonergic function.

Biol Psychiatry. 1997 Jan 15;41(2):196-200.
Low serum cholesterol in suicide attempters.
Kunugi H, Takei N, Aoki H, Nanko S.
Previous studies have shown an association between low serum cholesterol concentration and suicide; however, conflicting results have also been reported. To examine this potential association, cholesterol levels in 99 patients admitted to an emergency ward following an attempted suicide were compared with those in 74 nonsuicidal psychiatric inpatients, and those in 39 psychiatrically normal individuals with accidental injuries. Cholesterol concentrations in suicide attempters were found to be significantly lower compared with both psychiatric and normal controls, when sex, age, psychiatric diagnosis, and physical conditions (serum total protein and red blood cell count) were adjusted for. This significant relationship was observed in mood disorders and personality or neurotic disorders, but not in schizophrenia spectrum disorders. These results support the previous claim that lower cholesterol level is associated with an increased risk of suicidal behavior.

Psychosom Med. 1994 Nov-Dec;56(6):479-84.
Demonstration of an association among dietary cholesterol, central serotonergic activity, and social behavior in monkeys.
Kaplan JR, Shively CA, Fontenot MB, Morgan TM, Howell SM, Manuck SB, Muldoon MF, Mann JJ.
Epidemiologic studies link plasma cholesterol reduction to increased mortality rates as a result of suicide, violence, and accidents. Deficient central serotonergic activity is similarly associated with violence and suicidal behavior. We investigated the relationship among dietary and plasma cholesterol, social behavior, and the serotonin system as a possible explanation for these findings. Juvenile cynomolgus monkeys (eight female and nine male) were fed a diet high in fat and either high or low in cholesterol. We then evaluated their behavior over an 8-month period. Plasma lipids and cerebrospinal fluid metabolites of serotonin, norepinephrine, and dopamine were assessed on two occasions, at 4 and 5.5 months after the initiation of behavioral observations. Animals that consumed a low-cholesterol diet were more aggressive, less affiliative, and had lower cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid than did their high-cholesterol counterparts (p < .05 for each). The association among dietary cholesterol, serotonergic activity, and social behavior was consistent with data from other species and experiments and suggested that dietary lipids can influence brain neurochemistry and behavior; this phenomenon could be relevant to our understanding of the increase in suicide and violence-related death observed in cholesterol-lowering trials.

Ann N Y Acad Sci. 1997 Dec 29;836:57-80.
Assessing the observed relationship between low cholesterol and violence-related mortality. Implications for suicide risk.
Kaplan JR, Muldoon MF, Manuck SB, Mann JJ.
Health advocacy groups advise all Americans to restrict their dietary intake of saturated fat and cholesterol as an efficacious and safe way to lower plasma cholesterol concentrations and thus reduce the risk of coronary heart disease and other atherosclerotic disorders. However, accumulating evidence suggests that naturally low or clinically reduced cholesterol is associated with increased nonillness mortality (principally suicide and accidents). Other evidence suggests that such increases in suicide and traumatic death may be mediated by the adverse changes in behavior and mood that sometimes accompany low or reduced cholesterol. These observations provided the rationale for an ongoing series of studies in monkeys designed to explore the hypothesis that alterations in dietary or plasma cholesterol influence behavior and that such effects are potentiated by lipid-induced changes in brain chemistry. In fact, the investigations in monkeys reveal that reductions in plasma cholesterol increase the tendency to engage in impulsive or violent behavior through a mechanism involving central serotonergic activity. It is speculated that the cholesterol-serotonin-behavior association represents a mechanism evolved to increase hunting or competitive foraging behavior in the face of nutritional threats signaled by a decline in total serum cholesterol (TC). The epidemiological and experimental data could be interpreted as having two implications for public health: (1) low-cholesterol may be a marker for risk of suicide or traumatic death and (2) cholesterol lowering may have adverse effects for some individuals under some circumstances.

J Psychosom Res. 1995 Jul;39(5):549-62.
Cholesterol and psychological well-being.
Wardle J.
The debate about possible adverse effects associated with low or lowered serum cholesterol has raised important scientific questions concerning the links between lipids and behaviour. One of the most unexpected findings has been an association between cholesterol-lowering treatment and accidental death. A similar association has also emerged among the prospective cohort studies, with higher-than-expected numbers of suicide deaths in the lowest cholesterol groups. These observations have prompted speculation that behavioural or emotional disturbances could be part of the process linking lipids and accidental death. In this paper, the epidemiological literature is reviewed briefly, then the evidence for depression as a mediating condition is discussed. Two conclusions are drawn from this review of the literature. One is that understanding the relationship between the biology of lipids and the psychobiology of mood is demonstrably an important scientific and public health issue. The second is that the introduction of new treatments or preventive programmes should include a careful evaluation of the psychological as well as the physical effects.

Lancet. 1997 Oct 18;350(9085):1119-23.
Total cholesterol and risk of mortality in the oldest old.
Weverling-Rijnsburger AW, Blauw GJ, Lagaay AM, Knook DL, Meinders AE, Westendorp RG.
BACKGROUND:
The impact of total serum cholesterol as a risk factor for cardiovascular disease decreases with age, which casts doubt on the necessity for cholesterol-lowering therapy in the elderly. We assessed the influence of total cholesterol concentrations on specific and all-cause mortality in people aged 85 years and over.
METHODS:
In 724 participants (median age 89 years), total cholesterol concentrations were measured and mortality risks calculated over 10 years of follow-up. Three categories of total cholesterol concentrations were defined: < 5.0 mmol/L, 5.0-6.4 mmol/L, and > or = 6.5 mmol/L. In a subgroup of 137 participants, total cholesterol was measured again after 5 years of follow-up. Mortality risks for the three categories of total cholesterol concentrations were estimated with a Cox proportional-hazards model, adjusted for age, sex, and cardiovascular risk factors. The primary causes of death were coded according to the International Classification of Diseases (ICD-9).
FINDINGS:
During 10 years of follow-up from Dec 1, 1986, to Oct 1, 1996, a total of 642 participants died. Each 1 mmol/L increase in total cholesterol corresponded to a 15% decrease in mortality (risk ratio 0.85 [95% CI 0.79-0.91]). This risk estimate was similar in the subgroup of participants who had stable cholesterol concentrations over a 5-year period. The main cause of death was cardiovascular disease with a similar mortality risk in the three total cholesterol categories. Mortality from cancer and infection was significantly lower among the participants in the highest total cholesterol category than in the other categories, which largely explained the lower all-cause mortality in this category.
INTERPRETATION:
In people older than 85 years, high total cholesterol concentrations are associated with longevity owing to lower mortality from cancer and infection. The effects of cholesterol-lowering therapy have yet to be assessed.

Arch Intern Med. 2003 Jul 14;163(13):1549-54.
High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age.
Weverling-Rijnsburger AW, Jonkers IJ, van Exel E, Gussekloo J, Westendorp RG.
Abstract
BACKGROUND:
A high total serum cholesterol level does not carry a risk of cardiovascular mortality among people 85 years and older and is related to decreased all-cause mortality. At this old age, there are few data on fractionated lipoprotein levels in the determination of cardiovascular disease risk. The aim of this study was to evaluate the relationships between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels and mortality from specific causes among people in the oldest age categories.
METHODS:
Between September 1, 1997, and September 1, 1999, a total of 705 inhabitants in the community of Leiden, the Netherlands, reached the age of 85 years. Among these old people, we initiated a prospective follow-up study to investigate determinants of successful aging. A total of 599 subjects participated (response rate, 87%) and all were followed up to September 2001. Serum levels of total, LDL, and HDL cholesterol were assessed at baseline along with detailed information on comorbid conditions. The main outcome measure was all-cause and specific mortality risk.
RESULTS:
During 4 years of follow-up, 152 subjects died. The leading cause of death was cardiovascular disease, with similar mortality risks in all tertiles of LDL cholesterol level. In contrast, low HDL cholesterol level was associated with a 2.0-fold higher risk of fatal cardiovascular disease (95% confidence interval [CI], 1.2-3.2). The mortality risk of coronary artery disease was 2.0 (95% CI, 1.0-3.9) and for stroke it was 2.6 (95% CI, 1.0-6.6). Both low LDL cholesterol and low HDL cholesterol concentrations were associated with an increased mortality risk of infection: 2.7 (95% CI, 1.2-6.2) and 2.4 (95% CI, 1.1-5.6), respectively. The risks were unaffected by comorbidity.
CONCLUSION:
In contrast to high LDL cholesterol level, low HDL cholesterol level is a risk factor for mortality from coronary artery disease and stroke in old age.

Scand J Prim Health Care. 2010 Jun;28(2):121-7.
Serum total cholesterol levels and all-cause mortality in a home-dwelling elderly population: a six-year follow-up.
Tuikkala P, Hartikainen S, Korhonen MJ, Lavikainen P, Kettunen R, Sulkava R, Enlund H.
OBJECTIVE: To investigate the association between serum total cholesterol and all-cause mortality in elderly individuals aged > or = 75 years.
Design. A prospective cohort study with a six-year follow-up.
SETTING AND SUBJECTS: A random sample (n = 700) of all persons aged > or = 75 years living in Kuopio, Finland. After exclusion of participants living in institutional care and participants using lipid-modifying agents or missing data on blood pressure and cholesterol levels, the final study population consisted of 490 home-dwelling elderly persons with clinical examination. We used the Cox proportional hazard model and the propensity score (PS) method. Main outcome measure. All-cause mortality.
Results. In an age- and sex-adjusted analysis, participants with S-TC > or = 6mmol/l had the lowest risk of death (hazard ratio, HR = 0.48, 95% CI 0.33-0.70) compared with those with S-TC < 5 mmol/l. HR of death for a 1 mmol increase in S-TC was 0.78. In multivariate analyses, the HR of death for a 1 mmol increase in S-TC was 0.82 and using S-TC < 5 mmol/l as a reference, the HR of death for S-TC > or = 6 mmol/l was 0.59 (95% CI 0.39-0.89) and for S-TC 5.0-5.9 mmol/l, the HR was 0.62 (95% CI 0.42-0.93). In a PS-adjusted model using S-TC < 5 mmol/l as a reference, the HR of death for S-TC > or = 6 mmol/l was 0.42 (95% CI 0.28-0.62) and for S-TC 5.0-5.9 mmol/l, the HR was 0.57 (95% CI 0.38-0.84).
Conclusions. Participants with low serum total cholesterol seem to have a lower survival rate than participants with an elevated cholesterol level, irrespective of concomitant diseases or health status.

J Am Geriatr Soc. 2003 Jul;51(7):991-6.
Low total cholesterol and increased risk of dying: are low levels clinical warning signs in the elderly? Results from the Italian Longitudinal Study on Aging.
Brescianini S, Maggi S, Farchi G, Mariotti S, Di Carlo A, Baldereschi M, Inzitari D; ILSA Group.
OBJECTIVES:
To analyze the relationship between serum total cholesterol (TC) and all-cause mortality, taking into account various potential confounders.
DESIGN:
Population-based prospective cohort study.
SETTING:
Older Italians residing in the general community.
PARTICIPANTS:
Four thousand five hundred twenty-one men and women aged 65-84.
MEASUREMENTS:
Vital status data were available for 1992-95. The hazard ratios of dying for subjects in the second, third, and fourth quartiles compared with the first quartile of TC were computed using Cox proportional hazards, adjusting for lifestyle factors, anthropomorphic and biochemical measures, preexisting medical conditions, and frailty indicators.
RESULTS:
Blood samples were obtained from 3,295 (73%) of the participants, of whom 399 died during almost 3 years of follow-up. Low TC was associated with a higher risk of death. Those with TC in the second, third, and fourth quartiles (TC>189 mg/dL or 4.90 mmol/L) had lower hazard ratios (HRs) of death than subjects in the first quartile (0.57, 95% confidence interval (CI) = 0.38-0.87; 0.56, 95% CI = 0.36-0.88; and 0.53, 95% CI = 0.33-0.84, respectively). Few subjects taking lipid-lowering drugs (LLDs) were in the lowest quartile of cholesterol, suggesting that these individuals have low TC values for reasons other than LLD use.
CONCLUSION:
Subjects with low TC levels (<189 mg/dL) are at higher risk of dying even when many related factors have been taken into account. Although more data are needed to clarify the association between TC and all-cause mortality in older individuals, physicians may want to regard very low levels of cholesterol as potential warning signs of occult disease or as signals of rapidly declining health.

J Am Geriatr Soc. 2005 Feb;53(2):219-26.
Relationship between plasma lipids and all-cause mortality in nondemented elderly.
Schupf N, Costa R, Luchsinger J, Tang MX, Lee JH, Mayeux R.
OBJECTIVES:
To investigate the relationship between plasma lipids and risk of death from all causes in nondemented elderly.
DESIGN:
Prospective cohort study.
SETTING:
Community-based sample of Medicare recipients, aged 65 years and older, residing in northern Manhattan.
PARTICIPANTS:
Two thousand two hundred seventy-seven nondemented elderly, aged 65 to 98; 672 (29.5%) white/non-Hispanic, 699 (30.7%) black/non-Hispanic, 876 (38.5%) Hispanic, and 30 (1.3%) other.
MEASUREMENTS:
Anthropometric measures: fasting plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and non-HDL-C, body mass index, and apolipoprotein E (APOE) genotype. clinical measures: neuropsychological, neurological, medical, and functional assessments; medical history of diabetes mellitus, heart disease, hypertension, stroke, and treatment with lipid-lowering drugs. Vital status measure: National Death Index date of death. Survival methods were used to examine the relationship between plasma lipids and subsequent mortality in younger and older nondemented elderly, adjusting for potential confounders.
RESULTS:
Nondemented elderly with levels of total cholesterol, non-HDL-C, and LDL-C in the lowest quartile were approximately twice as likely to die as those in the highest quartile (rate ratio (RR)=1.8, 95% confidence interval (CI)=1.3-2.4). These results did not vary when analyses were adjusted for body mass index, APOE genotype, diabetes mellitus, heart disease, hypertension, stroke, diagnosis of cancer, current smoking status, or demographic variables. The association between lipid levels and risk of death was attenuated when subjects with less than 1 year of follow-up were excluded (RR=1.4, 95% CI=1.0-2.1). The relationship between total cholesterol, non-HDL-C, HDL-C, and triglycerides and risk of death did not differ for older (>or=75) and younger participants (>75), whereas the relationship between LDL-C and risk of death was stronger in younger than older participants (RR=2.4, 95% CI=1.2-4.9 vs RR=1.6, 95% CI=1.02-2.6, respectively). Overall, women had higher mean lipid levels than men and lower mortality risk, but the risk of death was comparable for men and women with comparable low lipid levels.
CONCLUSION:
Low cholesterol level is a robust predictor of mortality in the nondemented elderly and may be a surrogate of frailty or subclinical disease. More research is needed to understand these associations.

Lancet. 2000 Sep 9;356(9233):930-3.
The endotoxin-lipoprotein hypothesis.
Rauchhaus M, Coats AJ, Anker SD.
The advent of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) has revolutionised the treatment of hypercholesterolaemia. Statin treatment, by lowering the atherogenic lipoprotein profile, reduces morbidity and mortality in patients with cardiovascular disease. Treatment with simvastatin causes a reduction of events of new-onset heart failure, but this may be attributable to properties other than its lipid-lowering effects. There is some evidence that lower serum cholesterol concentrations (as a surrogate for the totality of lipoproteins) relate to impaired survival in patients with chronic heart failure (CHF). Inflammation is a feature in patients with CHF and increased lipopolysaccharide may contribute substantially. We postulate that higher concentrations of total cholesterol are beneficial in these patients. This is potentially attributable to the property of lipoproteins to bind lipopolysaccharide, thereby preventing its detrimental effects. We hypothesise there is an optimum lipoprotein concentration below which lipid reduction would, on balance, be detrimental. We also propose that, in patients with CHF, a non-lipid-lowering statin (with ancillary properties such as immune modulatory and anti-inflammatory actions) could be as effective or even more beneficial than a lipid-lowering statin.

After the age of fifty, low cholesterol is clearly associated with an increased risk of dying from a variety of causes. A study of old women indicated that a cholesterol level of 270 mg. per 100 ml. was associated with the best longevity (Forette, et al., 1989). -Ray Peat, PhD

Lancet. 1989 Apr 22;1(8643):868-70.
Cholesterol as risk factor for mortality in elderly women.
Forette B, Tortrat D, Wolmark Y.
92 women aged 60 years and over (mean 82.2, SD 8.6) living in a nursing home and free from overt cancer were followed-up for 5 years. 53 died during this period; necropsy revealed cancer in only 1 patient. Serum total cholesterol at entry ranged from 4.0 to 8.8 mmol/l (mean 6.3, SD 1.1). Cox’s proportional hazards analysis showed a J-shaped relation between serum cholesterol and mortality. Mortality was lowest at serum cholesterol 7.0 mmol/l, 5.2 times higher than the minimum at serum cholesterol 4.0 mmol/l, and only 1.8 times higher when cholesterol concentration was 8.8 mmol/l. This relation held true irrespective of age, even when blood pressure, body weight, history of myocardial infarction, creatinine clearance, and plasma proteins were taken into account. The relation between low cholesterol values and increased mortality was independent of the incidence of cancer.

J Psychiatry Neurosci. 2016 Jan;41(1):56-69.
Serum lipid levels and suicidality: a meta-analysis of 65 epidemiological studies.
Wu S, Ding Y, Wu F, Xie G1, Hou J, Mao P.
BACKGROUND:
We conducted a systematic review and meta-analysis to determine the association between serum lipid levels and suicidality, as evidence from previous studies has been inconsistent.
METHODS:
We identified relevant studies by searching Medline, Web of Science, EMBASE, and the Cochrane Database of Systematic Reviews (1980 to Dec. 5, 2014). Studies assessing the association between serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and/or triglycerides (TG) levels and suicidality were included. We used a random-effects model to take into account heterogeneity among studies.
RESULTS:
We included 65 studies with a total of 510 392 participants in our analysis. Compared with the nonsuicidal patients, suicidal patients had significantly lower serum TC (weighted mean difference [WMD] -22.35, 95% confidence interval [CI] -27.95 to -16.75), LDL-C (WMD -19.56, 95% CI -26.13 to -12.99) and TG (WMD -23.40, 95% CI -32.38 to -14.42) levels, while compared with the healthy controls, suicidal patients had significantly lower TC (WMD -24.75, 95% CI -27.71 to -21.78), HDL-C (WMD -1.75, 95% CI -3.01 to -0.48) and LDL-C (WMD -3.85, 95% CI -7.45 to -0.26) levels. Furthermore, compared with the highest serum TC level category, a lower serum TC level was associated with a 112% (95% CI 40%-220%) higher risk of suicidality, including a 123% (95% CI 24%-302%) higher risk of suicide attempt and an 85% (95 CI 7%-221%) higher risk of suicide completion. The cut-off values for low and high serum TC level were in compliance with the categories reported in the original studies.
LIMITATIONS:
A major limitation of our study is the potential heterogeneity in most of the analyses. In addition, the suicidal behaviour was examined using different scales or methods across studies, which may further explain heterogeneity among the studies.
CONCLUSION:
We identified an inverse association between serum lipid levels and suicidality. More mechanistic studies are needed to further explain this association.