Research Notes: Hypocholesterolemia (Low Cholesterol)

J Am Coll Cardiol. 2004 Jun 2;43(11):2142-6.
Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal.
O’Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R.
Mid America Heart Institute, Cardiovascular Consultants, Kansas City, Missouri, USA.

The normal low-density lipoprotein (LDL) cholesterol range is 50 to 70 mg/dl for native hunter-gatherers, healthy human neonates, free-living primates, and other wild mammals (all of whom do not develop atherosclerosis). Randomized trial data suggest atherosclerosis progression and coronary heart disease events are minimized when LDL is lowered to <70 mg/dl. No major safety concerns have surfaced in studies that lowered LDL to this range of 50 to 70 mg/dl. The current guidelines setting the target LDL at 100 to 115 mg/dl may lead to substantial undertreatment in high-risk individuals.

Nippon Rinsho. 2001 Aug;59(8):1599-604.
Low serum cholesterol and suicidal behavior. [Article in Japanese]
Kunugi H.
Department of Psychiatry, Teikyo University School of Medicine.

An increasing number of studies have shown that low serum cholesterol levels are associated with a risk of suicidal, violent, and impulsive behaviors. This article reviewed the literature on this possible association. Several randomized controlled trials of lowering cholesterol interventions did not reduce total mortality in spite of reduced mortality due to coronary heart disease. This is partly attributable to an increased mortality rate of death due to suicide or accidents among individuals with lowered serum cholesterol. Cohort studies have shown that individuals with low serum cholesterol levels are more likely to present depressive symptoms and suicidal acts in later years than those with higher cholesterol levels. Many studies comparing suicidal and control subjects have found an association between low serum cholesterol and suicidal behavior. Although contradictive results are also reported, further studies are warranted to conclude the possible relationship between low or lowering serum cholesterol and suicidal behavior. Clinicians should be aware of potential effects of lowering cholesterol interventions on behavioral symptoms.

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.
Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina, USA.

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.

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.
Department of Comparative Medicine, Bowman Gray School of Medicine, Winston-Salem, NC.

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.

Am J Med Sci. 1994 Oct;308(4):218-25.
Hypocholesterolemia and affective disorders.
Glueck CJ, Tieger M, Kunkel R, Hamer T, Tracy T, Speirs J.
Cholesterol Center, Jewish Hospital, Cincinnati, Ohio 45229.

The authors’ specific aim was to assess hypocholesterolemia in 203 patients hospitalized because of affective disorders (depression, bipolar disorder, and schizoaffective disorder) compared with 1,595 self-referred subjects in an urban supermarket screening and with 11,864 subjects in the National Health and Nutrition Examination Survey II, a national probability sample. Low plasma cholesterol concentrations (< 160 mg/dL) were much more common in patients with affective disorders (20%) than in urban supermarket screenees (4%, P < or = 0.001) or in the National Health and Nutrition Examination Survey II subjects (10%, P < or = 0.001). When paired with supermarket screenees by age and sex, patients with affective disorders had much lower plasma total cholesterol (P < or = 0.0002), low-density lipoprotein cholesterol (P < or = 0.001), and high-density lipoprotein cholesterol (P < or = 0.0001), and higher triglyceride concentrations (P < or = 0.03). Neither the severity of the affective disorders nor severity-age interactions were associated with plasma cholesterol concentrations (P > 0.1); age and plasma cholesterol were positively associated (P = 0.01). None of the psychoactive drugs had a significant independent association with the patients’ low-density lipoprotein cholesterol. Plasma cholesterol in patients hospitalized with affective disorders is shifted markedly downward toward hypocholesterolemic concentrations (< 160 mg/dL). There is no evidence that low plasma cholesterol could cause or worsen affective disorders.