comentários 
13 de Junho, 2009
Deformidades congénitas, distúrbios psicológicos, atrasos mentais, comportamentos violentos, disfunções cerebrais, depressão, tendências suicidas, maior mortalidade e outras condições associadas a baixos níveis de colesterol
Cholesterol and psychological well-being.
Health Behaviour Unit, Institute of Psychiatry, University of London, UK.
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.
Low serum cholesterol and suicidal behavior
[Article in Japanese]
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.
Low concentration level of total serum cholesterol as a risk factor for suicidal and aggressive behavior
[Article in Polish]
Kliniki Psychiatrii Dorosłych AM w Poznaniu.
The data have been presented for possible association between low total serum cholesterol concentration and the increased risk of suicidal and aggressive behavior. The analysis of results from some long-term epidemiological studies shows an excess of suicides and violent death cases among persons with low baseline total serum cholesterol level and in those in whom this level was lowered by means of pharmacotherapy or dieting. In patients hospitalized on psychiatric wards, having low total serum cholesterol concentration, a higher intensity of suicidal thoughts and tendencies was found. Such relationship was most evident in patients with depression. In some populations, an association between low total cholesterol level and the tendency to aggressive behavior was also found. Higher intensity of aggression was also observed in animals receiving low-cholesterol diet. A hypothesis was discussed, postulating the connection between low cholesterol level and lower activity of central serotonergic structures responsible for the inhibition of impulsive behavior.
Neurobiological correlates of suicidal behavior
[Article in German]
Max-Planck-Institut für Psychiatrie, München.
Studies in postmortem brain tissue from suicide victims show a presynaptic serotonergic deficit resulting in compensatory upregulation of postsynaptic 5-HT2 receptors in the prefrontal cortex. Reduced levels of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid, the major serotonin metabolite, are associated with violent suicide attempts independent of psychiatric diagnosis and predict future suicide attempts and suicide completion, consistent with the notion of a biochemical trait. Neuroendocrine challenge tests, platelet studies and a polymorphism in the gene for tryptophan hydroxylase, the rate-limiting enzyme in the biosynthesis of serotonin, suggest that serotonergic activity may be reduced. This serotonergic abnormality might be related to the vulnerability or diathesis for suicidal behaviour by predisposing individuals to impulsive and autoaggressive behaviour. The hypothesis of hyperactivity of the hypothalamic pituitary adrenal axis (HPA) is supported by the postmortem findings of increased CSF corticotropin releasing hormone (CRH) concentrations and reduced CRH receptor binding sites in the frontal cortex of suicide victims (interpreted as downregulation following CRH hypersecretion) and dexamethasone nonsuppression in suicide attempters. Animal studies and in vitro experiments indicate that the HPA system modulates serotonergic activity. It is hypothesized that the serotonergic alterations potentially result from dysregulation of the HPA system. Data from epidemiological and clinical studies demonstrate that low levels of cholesterol are associated with increased suicide risk. In neuronal membranes cholesterol modulates presynaptic and postsynaptic serotonergic neurotransmission. In monkeys dietary cholesterol lowering inhibits central serotonergic activity and predisposes the animals to impulsive and aggressive behaviour. It is speculated that dysregulation of the HPA system and disordered cholesterol metabolism could enhance the serotonergic deficit, thus contributing to a neurobiological vulnerability or diathesis for impulsive and autoaggressive behaviour.
Cholesterol and mental disorder.
Department of Psychiatry, Faculty of Medicine, University of Leicester.
BACKGROUND: Cholesterol plays an important part in cellular structure and function and changes in serum levels may affect neurotransmission in the central nervous system. METHOD: A MEDLINE literature search was made covering the period 1990-95 with systematic searching of citations from the articles identified. Representative articles were selected, focusing on those aspects which had not been thoroughly reviewed elsewhere, namely suicidal ideation, depression, personality and schizophrenia. RESULTS: Lowering cholesterol levels have been associated with an increase in violent deaths in cardiovascular primary prevention studies. However, altered cholesterol levels have also been reported in relation to other psychiatric disorders. CONCLUSION: There is substantial evidence that serum cholesterol levels may be associated with variations in mental state or personality. Further work is needed to clarify this and to elucidate the mechanisms involved.
The association of low serum cholesterol with depression and suicidal behaviours: new hypotheses for the missing link.
Department of Clinical and Experimental Medicine, University of Ferrara, Italy.
Several observational studies indicate that reduction of serum cholesterol levels is related to an increase in violent deaths and suicide but the nature of this possible relationship remains unclear. Many confounding factors, e.g. poor health, depression and loss of appetite may play a role in the apparent relationship between serum cholesterol levels and suicide. Two separate phenomena should be considered: lowering total cholesterol and low total cholesterol. This review considers the evidence from epidemiological studies on serum cholesterol lowering and psychiatric disturbances. The available evidence does not seem to substantiate the view that large-scale intervention to reduce cholesterol concentrations could lead to more violent and aggressive behaviour, and generally greater unhappiness. In recent trials using statin treatment, there were slightly fewer deaths from accidents and suicide in the treated group compared with the placebo group. We believe that clinicians should not be deterred from prescribing cholesterol-lowering drugs, to reduce the risk of death from coronary heart disease, when they are indicated.
Cholesterol in mood and anxiety disorders: review of the literature and new hypotheses.
Depression Clinical and Research Program, Department of Psychiatry, Massachusetts General Hospital, 15 Parkman Street, WACC #812, Boston, MA 02114, USA.
Cholesterol plays an integral role in the structure and function of the cell membrane and may also affect neurotransmission in the central nervous system. Previous work has identified abnormalities in serum cholesterol levels in patients with mood and anxiety disorders as well as in suicidal patients. However, the biological significance of these abnormalities remains to be clarified. An understanding of how serum cholesterol relates to the pathophysiology of mood disorders may generate biological markers that predict treatment response as well as targets for novel therapeutic strategies. In this article, we review the literature studying the significance of cholesterol in mood and anxiety disorders, with an emphasis on new studies focusing on the adverse impact of hypercholesterolemia on the treatment of major depressive disorder (MDD). We then propose possible mechanisms that would account for the relationship between elevated cholesterol and treatment non-response in MDD.
Relation between cholesterol levels and neuropsychiatric disorders
[Article in Spanish]
Centro Penitenciario de Jóvenes de Barcelona, Generalitat de Catalunya, Sant Joan de Déu, Barcelona, España.
INTRODUCTION: A recent survey raised doubts about most of the associations between hypercholesterolemia and neuropsychiatric diseases. Nevertheless, there is scientific evidence (some very recent) that demonstrates a link between possible brain disorders and reduced levels of cholesterol. AIM. To conduct a systematic study of the literature that addresses the relation between low cholesterol levels in serum and neuropsychiatric disorders. DEVELOPMENT: Relevant papers were identified by means of a systematic search and selection of the literature on Medline (August 2008). The selected papers were reviewed using statistical analysis and critical-deductive reasoning. CONCLUSIONS: It is shown that low cholesterol levels in serum are associated and related to different neuropsychiatric disorders. Lowered cholesterol levels seem likely to be linked to higher rates of early death, suicide, aggressive and violent behaviour, personality disorders, and possibly depression, dementia and penal confinement among young males. Further studies are needed to confirm the evidence currently available and to relate more accurate diagnoses with hypercholesterolemia.
Assessing the observed relationship between low cholesterol and violence-related mortality. Implications for suicide risk.
Comparative Medicine Clinical Research Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157-1040, 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.
Cholesterol and violent behavior.
Department of Psychiatry, University of Arizona College of Medicine, Tucson.
Despite significant decreases [corrected] in the incidence of myocardial infarction, reduction of total mortality as a result of cholesterol-lowering programs has not been demonstrated. This puzzling outcome has led to several hypotheses linking cholesterol levels and mortality due to accidents, suicide, and homicide. We review the proposed explanations for increased mortality due to violent deaths. We discuss the available evidence and conclude that while there are some intriguing findings based on the well-established relationship between violent behavior and serotonin activity, the necessary link between cholesterol, serotonin, and violence has not been demonstrated. The complexity of the observed violent behaviors and their multiple determinants defies a simple explanation at the present time.
Cholesterol and violence: is there a connection?
University of California, Los Angeles, USA.
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.
Significance of cholesterol levels in patients 75 years or older
[Article in French]
Université Victor Segalen, Bordeaux 2, département de médecine gériatrique, Hôpital Xavier Arnozan, Centre Henri Choussat, Pessac.
Increasing comorbidity with aging reduces the predictive power of cardiovascular risk factors. From the age of 70 onward, total cholesterol levels decrease, perhaps associated with changes in the composition of some lipoprotein fractions. In subjects older than 75 years, being in the lowest quartile of cholesterol, insulinemia or serum albumin concentrations is associated with increased mortality. Cholesterol levels below 189 mg/dL in subjects older than 75 years should be considered an early sign of unidentified comorbidity or of rapid functional decline. HDL cholesterol levels, rather than total or LDL cholesterol, were inversely associated with increased mortality from ischemic coronary disease and stroke appears to rise as HDL cholesterol levels fall, rather than total or LDL cholesterol. On the other hand, LDL concentrations below 106 mg/dL and HDL concentrations below 36 mg/dL were associated with an increased risk of death from infectious disease. Stroke incidence, in particular, ischemic stroke, is highest in subjects older than 75 years. HDL cholesterol levels above 35 mg/dL appear to have a protective effect against ischemic stroke in subjects younger than 70 years. Two interventional drug studies investigating the effects of two statins (simvastatin and pravastatin) found that in subgroups of subjects older than 75 these drugs were associated with a reduction in all-cause mortality and cardiovascular morbidity, regardless of total cholesterol levels, but had no short-term effect on cognitive function.
The role of cholesterol in Alzheimer’s neuro-pathogenesis
[Article in Italian]
Alzheimer’s Disease (AD) is the most common neurodegenerative disorder in western societies affecting up to 15 million individuals worldwide.It leads to death after a progressive memory deficit and cognitive impairment accompanied by the appearance of two pathological hallmarks in specific brain areas: neurofibrillary tangles and amyloid plaques. Cholesterol homeostasis may play a key role in AD pathogenesis and this is supported by the demonstration that cholesterol-rich membrane domain, so-called Rafts,are disorganized in affected brains. Retrospective clinical studies indicate that individuals chronically treated with cholesterol synthesis inhibitors,statins, are at lower risk of developing AD but current literature is conflicting with regard to the neuroprotective effects of statins on cognitive impairment.Before recommending statins for prevention and/or treatment of AD it is important to investigate more the role of cholesterol levels in neurodegenerative disorders.
Cholesterol in coronary heart disease and psychiatric disorders: same or opposite effects on morbidity risk?
Department of Neurosciences, University of Tor Vergata, via Guattani 14, 00161 Rome, Italy.
The goal of this article is to review the studies that have linked low cholesterol levels with psychiatric symptoms or behavioral disorders in order to clarify which cholesterol fractions may influence psychological well being and mental health. The distinction between "bad" (i.e., pro-atherogenic) and "good" (i.e., anti-atherogenic) cholesterol is crucial to decide if the clinical benefits of low cholesterol levels for cardiovascular health might turn into a risk factor for psychiatric morbidity. Although the data from studies linking low cholesterol to aggression, suicide and self-harm, impulsivity, negative mood, postnatal depression, and cognitive dysfunction are far from unequivocal, the balance of evidence from new randomized controlled trials is reassuring. However, there are some subgroups of vulnerable individuals who, unlike the majority of persons in the general population, are susceptible to the psychological and behavioral adverse outcomes associated with low cholesterol levels. Because in some cases pro-atherogenic lipid and lipoprotein fractions are involved in this vulnerability, reaching the double goal of promoting both cardiovascular and mental health may be problematic for some individuals. A major task of future research is to identify these vulnerable individuals.
Cholesterol lowering, sudden cardiac death and mortality.
Laboratoire TIMC IMAG CNRS UMR 5525, Groupe PRETA Coeur et Nutrition, Faculté de Médecine, La Tronche (Grenoble), France.
Sudden cardiac death is the main cause of cardiac mortality. Is blood cholesterol a determinant of sudden cardiac death? Does cholesterol lowering result in fewer sudden cardiac deaths? Answering these two questions may shed a new light on the epidemiology of coronary heart disease and on prevention options. In fact, careful analysis of the available data, including randomised trials, indicates that, contrary to a widespread opinion, cholesterol lowering does not appear to be a very effective way of reducing cardiac and overall mortality in the general population.
Low cholesterol and noncardiovascular mortality.
University of Texas Health Science Center at San Antonio, USA.
Recent clinical trial data have suggested that low cholesterol might cause increased mortality from noncardiovascular conditions. Several randomized trials have suggested an increase in noncoronary deaths at low levels of total cholesterol. When subcategories for causes of death were investigated, it was noted that hemorrhagic stroke risk was inversely related to total cholesterol, whereas nonhemorrhagic stroke risk was positively related to total cholesterol. Certain cancers were shown to be more common at low total cholesterol levels, namely lung, liver, lymphatic, and hematopoietic cancer. Another issue to consider is whether increased mortality rates are seen in individuals with "naturally" occurring low cholesterol or whether they are seen in individuals whose cholesterol has been deliberately lowered through dietary or drug intervention, or in both. If an association between low cholesterol and noncardiovascular mortality is present, there is continuing uncertainty regarding the mechanism by which it occurs.
Cholesterol reduction therapy: a double-edged knife.
Gleneagles Medical Centre, Penang.
Cholesterol reduction reduces ischaemic cardiovascular morbidity and mortality in the asymptomatic healthy population as well as in those with known coronary artery disease. Angiographic studies have also demonstrated regression of atherosclerotic plaques as well as retardation of new atheroma formation with such therapy. Yet, there is a consistent inability to reduce overall mortality in cholesterol-lowering drug trials. An excess of suicide, homicide and violence has been attributed to cholesterol reduction interfering with membrane lipids and receptors, leading to aggressive behaviour. The risk and benefits of cholesterol reduction must thus be weighed in the individual patient; it is more useful in those with known coronary artery disease who are at high risk of subsequent ischaemic cardiovascular events.
Lipid-protein interactions, regulation and dysfunction of brain cholesterol.
Centre for Cellular and Molecular Biology, Uppal Road, Hyderabad 500 007,
The biosynthesis and metabolism of cholesterol in the brain is spatiotemporally and developmentally regulated. Brain cholesterol plays an important role in maintaining the function of neuronal receptors, which are key components in neural signal transduction. This is illustrated by the requirement of membrane cholesterol for the function of the serotonin(1A) receptor, a transmembrane neurotransmitter receptor. A crucial determinant for the function of neuronal receptors could be the availability of brain cholesterol. The Smith-Lemli-Optiz Syndrome, a metabolic disorder characterized by severe neurodegeneration leading to mental retardation, represents a condition in which the availability of brain cholesterol is limited. A comprehensive molecular analysis of lipid-protein interactions in healthy and diseased states could be crucial for a better understanding of the pathogenesis of psychiatric disorders.
Cholesterol dysfunction in neurodegenerative diseases: is Huntington’s disease in the list?
Department of Pharmacological Sciences and Centre for Stem Cell Research, Via Balzaretti 9, 20133 Milano, Italy.
Brain cholesterol is an essential component of cell membranes, and involved in a number of biological functions such as membrane trafficking, signal transduction, myelin formation and synaptogenesis. Given these widespread activities and the knowledge that all brain cholesterol derives from local synthesis, it is not surprising that dysfunctions in cholesterol synthesis, storage, transport and removal may lead to human brain diseases. Some of these diseases emerge as a consequence of genetic defects in the enzymes involved in cholesterol biosynthesis; in other cases, such as Alzheimer’s disease, there is a link between cholesterol metabolism and the formation and deposition of amyloid-beta peptide. Emerging evidence indicates that changes in cholesterol synthesis may also occur in Huntington’s disease, an inherited, autosomal dominant neurodegenerative disorder that primarily affects striatal neurons of the brain. We here provide an overview of the involvement of cholesterol in normal brain function and its impact on neurodegenerative diseases. In particular, we consider the available clinical, biological and molecular evidence indicating a potential dysregulation of cholesterol homeostasis in Huntington’s disease.
Low serum cholesterol and the risk of cerebral haemorrhage.
Department of Medicine, University of Western Australia, Perth.
In addressing the potential for any hazards associated with lowering serum cholesterol, a recent meta-analysis by Law and colleagues (Br Med J 1994;308:373) concluded that that there was no evidence that a low or reduced serum cholesterol concentration increases mortality from any cause other than haemorrhagic stroke. In this review, the evidence for this unexpected association will be addressed, and possible mechanisms discussed. Overall implications of the phenomenon, particularly for the hypertensive patient, will be addressed in the context of the anticipated consequences of lipid-lowering therapy for all stroke, haemorrhagic and non-haemorrhagic, as well as ischaemic heart disease (IHD).
Epidemiological remarks on low serum cholesterol level and cancer risk of all sites
[Article in Japanese]
Department of Preventive Medicine, Nagoya University School of Medicine.
Epidemiological studies which examine an association between low serum cholesterol level and cancer risk of all sites were reviewed and a summary of major findings are as follows: (1) In most reports, low serum cholesterol level, which associated with cancer of all sites, cancer deaths/incidence occurred within a few years after cholesterol measurement were performed. This short-term association is believed to be a preclinical cancer effect, i.e., preclinical cancer itself reduces serum cholesterol level. (2) A long-term inverse association between serum cholesterol and cancer risk of all sites was observed in some studies. This association cannot be explained by either a preclinical cancer effect or by chance. The epidemiological implications of this association was discussed in depth. (3) A long-term inverse association between serum cholesterol level and cancer mortality/incidence was observed mainly in men, but not in women. In a few studies which reported an inverse association in women, follow-up periods were rather short. (4) A few epidemiological studies conducted in Japan also detected a long-term inverse relationship between serum cholesterol level and cancer risk of all sites in men, but not in women. Since low serum cholesterol level may possibly be a risk factor for cancer of all sites, further investigation involving experimental studies on animals and longitudinal population-based study appear to be necessary for confirmation of this factor.
Serum cholesterol and cancer risk: an epidemiologic perspective.
Department of Biostatistics and Epidemiology, University of Tennessee, Memphis 38163.
This review has examined the evidence surrounding two questions: (a) Is having low serum cholesterol associated with increased risk of cancer? (b) Does reducing serum cholesterol increase the occurrence of cancer? Some elevated risk of cancer for males with low serum cholesterol levels has been noted: the median of the studies examined is consistent with a 30% increased risk. The answer for females is less clear. The median of the studies examined suggests no more than a 5-10% increased risk associated with having low serum cholesterol. However, the risk seems to depend strongly on whether females have a central or peripheral body fat pattern (54). The cancers most consistently associated with low serum cholesterol levels are those of the colon and lung in males, the cervix and breast (but only for females under 50 years of age) in females, and leukemia in both sexes. In contrast, high cholesterol levels have been linked with an increase in brain cancer. While immunologic, genetic, and dietary explanations have been offered to explain the association, it is difficult to support the idea that low serum cholesterol causes cancer in any direct manner. First, the findings themselves tend to be generally weak and somewhat inconsistent. Second, the strong influence of fat distribution in women suggests that a metabolic/hormonal basis underlies the association. One would not expect the results to differ by body fat pattern if the relationship were a causal one. Finally, if there were a direct causal role, one would expect populations with low serum cholesterol levels to have higher cancer rates. In China, counties with the lowest average plasma cholesterol levels have the lowest cancer rates (78). While this observation is open to a number of interpretations, it does not support the idea that low serum cholesterol is a tumor initiator. In aggregate, the trials of lipid-lowering interventions reviewed here show an increase in cancer occurrence (primarily mortality) of approximately 24% in the cholesterol-lowered groups. However, the post-trial experience has shown a comparative deficit of cancer occurrence in the experimental groups. Recent evidence indicates that products in the cholesterol biosynthetic pathway affect DNA replication and cell proliferation. These findings suggests a mechanism by which cholesterol lowering might accelerate the development of tumors already initiated. The data that have been reviewed in no way suggest that treatment of hypercholesterolemia should not be pursued. They do suggest the presence of a relatively small subpopulation in whom reduction of plasma cholesterol may lead to increased occurrence of cancer.
Relationship between low cholesterol and disease. Evidence from epidemiological studies and preventive trials.
Institute of Social and Preventive Medicine, University of Zürich, Switzerland.
This review has addressed the concern that the reduction of the risk of coronary heart disease and other cardiovascular disorders by means of reducing serum cholesterol levels might, at the same time, increase the risk of developing noncardiovascular conditions. This concern is justified because, at face value, prospective epidemiological studies indicate that total mortality and mortality from a number of specific causes of death increase below a threshold value of serum cholesterol (the J-shaped curve phenomenon) and intervention studies to date have mostly failed to show a decrease of total mortality in the experimental group, despite a fall in coronary heart disease mortality (suggesting an increase in noncardiac mortality). Detailed scrutiny of the evidence from prospective studies provides no convincing evidence that low cholesterol levels are associated with an excess of deaths from cancer, except possibly to a minor degree; excess mortality from other causes which account for only a minority of all deaths, are in all likelihood confounded by influences that, in themselves, increase the probability of dying. Preventive trials that have been designed to test whether reduction of serum cholesterol will lower heart disease risk have, so far, provided insufficient numbers of noncardiovascular deaths to test, in addition, whether serum cholesterol lowering is accompanied by an increase in such deaths. According to available evidence, both the apparent excess of noncardiac deaths and total mortality could be attributable to chance. In the light of these findings from prospective studies and preventive trials, as well as the cross-cultural, ecological data that have been summarized, the total evidence provides no justification for depriving either high-risk individuals or populations at high risk as a whole of the benefits of serum cholesterol reduction for preventing heart disease on the grounds that such reduction may increase the risk of noncardiovascular conditions. This latter risk is far from being established and, if present, from all the available evidence is much smaller than the risk of withholding protection from persons and populations exposed to elevated coronary heart disease risk. In addition to the conclusions from epidemiological and intervention studies, a paramount question relates to the biological plausibility of causal connections between low or lowered cholesterol and the hazard of noncardiovascular disorders. Assessment of currently available data provides no evidence for the existence of mechanisms that might explain such a link. Countries in which average serum cholesterol levels are still low, as in Japan, face a different problem.
The cholesterol controversy.
Department of Pharmacy Practice, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
OBJECTIVE: To provide information about the controversy associated with lowering of cholesterol concentrations to prevent coronary heart disease (CHD). DATA SOURCES: Studies, review articles, and editorials identified from MEDLINE searches (from 1966 to 1995) and bibliographies of identified articles. STUDY SELECTION: Studies, review articles, and editorials addressing controversial issues related to cholesterol lowering. DATA EXTRACTION: Pertinent information was selected and the data synthesized into a review format. DATA SYNTHESIS: Hypercholesterolemia is a well-known CHD risk factor. Reduction of serum cholesterol concentrations has been shown to reduce the incidence of CHD. Unfortunately, cholesterol lowering also appears to increase the risk for cancer, accidental and violent death, stroke, and oddly enough, CHD when certain medications are used. CONCLUSIONS: Significant reductions in serum cholesterol concentrations can be achieved with cholesterol-lowering interventions. However, the benefits associated with cholesterol reduction may not outweigh the risks in all patients with hypercholesterolemia. Cholesterol-lowering interventions should be recommended with caution in patients at increased risk of cancer, stroke, and depression. Caution should also be used when recommending fibric acid derivatives for patients with existing CHD.
Inborn errors of cholesterol biosynthesis.
Johns Hopkins University, Baltimore, Md., USA.
Disorders of cholesterol biosynthesis have recently emerged as important errors of metabolism that collectively have taught us many new genetic and biochemical lessons. Whereas most metabolic diseases are characterized by exclusively or largely postnatal biochemical toxicities or deficiencies, disorders of cholesterol biosynthesis are notable for their severe effects on prenatal development. The remarkable embryonic consequences of abnormal cholesterol biosynthesis are exemplified by Smith-Lemli-Opitz syndrome (SLOS), a well-known multiple congenital anomaly syndrome only recently discovered to be caused by a deficiency in the last step in cholesterol biosynthesis. Equally surprising has been the discovery that primary defects of cholesterol biosynthesis cause several different forms of congenital skeletal dysplasia, most notably X-linked dominant chondrodysplasia punctata, or Conradi-Hünermann syndrome. Yet another sterol disorder, desmosterolosis, caused by defective activity of desmosterol reductase, combines a severe osteosclerotic skeletal dysplasia with multiple embryonic malformations similar to those of SLOS. The discovery of the biochemical basis of these diverse genetic disorders has provided not only accurate biochemical methods for their diagnosis and prenatal diagnosis, but also new insights into the biochemistry of vertebrate embryonic development. Among the lessons we have learned from the study of inborn errors of cholesterol biosynthesis, one of the most important is that the abnormal cholesterol metabolism of SLOS impairs the function of "Sonic hedgehog" and other related embryonic "signaling proteins" that help determine the vertebrate body plan during the earliest weeks of embryonic development. Most significant clinically has been the realization that many of the postnatal clinical problems of patients with SLOS are direct consequences of the inability to synthesize the large amounts of cholesterol needed for growth and for the synthesis of compounds derived from cholesterol, such as steroid hormones. In addition to the important finding that supplementary cholesterol eliminates or ameliorates many of the feeding and growth problems of SLOS, the discovery that the autistic behaviors of children with SLOS can be reduced or even eliminated by treatment with supplementary dietary cholesterol has been one of the most startling. Moreover, clinical and basic research on prenatal cholesterol nutrition in SLOS and various animal model systems has delineated a previously unrecognized system for the delivery of low-density lipoprotein cholesterol from the mother to the developing embryo. The many discoveries engendered by these experiments of nature argue that there are heretofore unrecognized beneficial effects of cholesterol, especially in children, and that we should consider very carefully possible adverse effects that the popular war against cholesterol may have on the prenatal and postnatal development of children.
Abnormal cholesterol biosynthesis in sitosterolaemia and the Smith-Lemli-Opitz syndrome.
VA Medical Center, East Orange, NJ 07018, USA.
We investigated the enzyme defects in two inherited disorders of cholesterol biosynthesis: sitosterolaemia and the Smith-Lemli-Opitz syndrome. In sitosterolaemic homozygotes, plasma plant sterols (sitosterol and campesterol) concentrations are elevated because of enhanced intestinal absorption and diminished removal. Underlying these changes is very low cholesterol biosynthesis to provide extra sterol for cell growth. Extremely reduced activities of HMG-CoA reductase, the rate-controlling enzyme for cholesterol biosynthesis, caused by deficient HMG-CoA reductase mRNA is responsible and is the suspected inherited abnormality. The Smith-Lemli-Opitz syndrome is caused by a block in the last reaction in the cholesterol biosynthetic pathway, the conversion of 7-dehydrocholesterol to cholesterol, which is catalysed by 7-dehydrocholesterol delta 7-reductase. As a result, low plasma and tissue cholesterol with high 7-dehydrocholesterol levels are found in homozygotes, who show characteristic phenotypes of mental retardation, facial dysmorphism, and organ and limb congenital anomalies. Similar biochemical findings are produced in rats fed BM 15,766, an inhibitor of 7-dehydrocholesterol delta 7-reductase. Interestingly, feeding cholesterol can suppress abnormal cholesterol biosynthesis and improve symptoms in homozygotes and rats fed BM 15,766.
Smith-Lemli-Opitz syndrome: the first malformation syndrome associated with defective cholesterol synthesis.
Department of Pediatrics, Oregon Health Sciences University, Portland, Oregon 97201, USA.
Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol reductase (DHCR7). Clinical signs vary in severity, ranging from fetal loss to holoprosencephaly with multiple malformations to isolated syndactyly. The biochemical defect in SLOS is a deficiency of DHCR7, which results in an abnormally low cholesterol level, and increased amounts of intermediates of sterol biosynthesis. Animal models currently exist through the use of cholesterol biosynthesis inhibitors, from which a great deal has been learned. Pregnant rats treated with inhibitors of DHCR7 yield pups that have abnormal sterol profiles and craniofacial abnormalities characteristic of severe SLOS. Biochemical testing of human patients can be performed using gas chromatography/mass spectroscopy (GC/MS) to analyze the sterol content of tissues, amniotic fluid, or cell culture lysate. Numerous mutations have been identified in DHCR7 but seven individual mutations account for 67% of the total mutations reported in the literature. Clinical trials with SLOS are underway, with the goal of increasing the cholesterol concentration in the plasma and tissues through the administration of dietary cholesterol. Thus far, this approach has shown limited efficacy. Nevertheless, the recent identification of the biochemical and molecular genetic basis for SLOS is reason for optimism that the condition may one day yield to treatment. Copyright 2000 Academic Press.
Human malformation syndromes due to inborn errors of cholesterol synthesis.
Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA.
PURPOSE OF REVIEW: This review covers a group of human malformation syndromes, which are caused by inborn errors of cholesterol synthesis. The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple malformation, and mental retardation syndrome that is the prototypical example of this group of disorders. In the 10 years since the biochemical cause of SLOS was identified, other malformation syndromes have been shown to result from defects in this pathway. These include desmosterolosis, lathosterolosis, X-linked dominant chondrodysplasia punctata type 2 (CDPX2), congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD syndrome), hydrops-ectopic calcification-moth-eaten skeletal dysplasia (HEM dysplasia), and some cases of Antley-Bixler syndrome. These disorders represent the first true merging of dysmorphology with biochemical genetics. RECENT FINDINGS: Recent studies report the identification of human lathosterolosis patients, indicate that SLOS is a relatively common genetic disorder that may be a major unrecognized cause of fetal loss, suggest that correction of the biochemical defect can improve central nervous system function, and show that perturbed sonic hedgehog signaling due to decreased sterol levels likely underlies some of the malformations in SLOS and lathosterolosis. SUMMARY: Recognition of the biochemical defect in these syndromes has given insight into the role that cholesterol plays during normal development, into understanding the pathophysiological processes that underlie the clinical problems found in these disorders, and into developing therapeutic interventions.
Disorders of cholesterol biosynthesis: prototypic metabolic malformation syndromes.
Center for Molecular and Human Genetics, Columbus Children’s Research Institute and Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA.
Since 1998, five disorders involving enzyme defects in post-squalene cholesterol biosynthesis have been identified-desmosterolosis, X-linked dominant chondrodysplasia punctata, CHILD syndrome, lathosterolosis, and hydrops-ectopic calcification-moth-eaten skeletal dysplasia. They join the most common cholesterol biosynthetic disorder, Smith-Lemli-Opitz syndrome, whose underlying defect was identified in 1993. All are associated with major developmental malformations that are unusual for metabolic disorders. The existence of mouse models for five of these disorders is beginning to enable more detailed developmental and in vitro studies examining the mechanisms involved in disease pathogenesis. In this review, an overview of the cholesterol biosynthetic pathway will be presented. Clinical features of the human disorders and mouse models of post-squalene cholesterol biosynthesis will then be discussed.
A new approach to cholesterol
[Article in Slovak]I. detská klinika Detskej fakultnej nemocnice, Bratislava, SR.
Although much is known about hypercholesterolemia and the associated risk for the development of atherosclerosis, very little research has focused on altered cholesterol biosynthesis. Recent discovery that the biochemical basis for the human malformation syndrome, Smith-Lemli-Opitz syndrome appears to lie in altered cholesterol biosynthesis has changed this situation. Cholesterol has an extraordinary important functions in organism. Recommendations to lower serum cholesterol are widespread, yet low serum cholesterol is associated with poorly understood morbidity. Cholesterol is still an enigmatic, essential metabolite and much remains to learn about it.
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