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Low Serum Cholesterol

Low Serum Cholesterol

Hazardous to Health?
1. Elaine N. Meilahn [1], MD + Author Affiliations 1. From the London School of Hygiene and Tropical Medicine, Department of Epidemiology, University of London, London. 1. Correspondence to Elaine N. Meilahn, MD, the London School of Hygiene and Tropical Medicine, Department of Epidemiology, University of London, Keppel Street, London WC1E 7HT, UK. Key Words: Is having very low cholesterol levels hazardous to health? There is evidence to suggest that it might be. In 1990, an NIH conference concluded from a metaanalysis of 19 studies that men and, to a lesser extent, women with a total serum cholesterol level below 4.2 mmol/L (160 mg/dL) (6th percentile) exhibited about a 10% to 20% excess total mortality compared with those with a cholesterol level between 4.2 and 5.2 mmol/L (160 to 199 mg/dL).1 Specifically, excess causes of death included cancer (primarily lung and hematopoietic), respiratory and digestive disease, violent death (suicide and trauma), and hemorrhagic stroke. On the basis of this and other reports, a debate arose on whether recommendations for lowering cholesterol should be directed at the entire population or only toward those at high risk of coronary heart disease. Would shifting the entire cholesterol distribution downward subject those individuals at the low end of the scale to increased risk of noncardiovascular disease?2 3 A major obstacle to finding an answer to this question has been that the determinants of low cholesterol are poorly understood. Why does someone living in a westernized country have a very low serum cholesterol
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concentration? Apart from consuming an atypical very-low-fat, lowcholesterol diet, the reasons include genetic resistance to excess dietary cholesterol,4 an underlying condition causing hypocholesterolemia such as an acute infection5 or preclinical disease,6 or, possibly, adverse health behavior such as alcohol abuse.7 Epidemiological studies generally have been unable to distinguish individuals with low cholesterol caused by underlying disease or aberrant health habits from those with naturally occurring low cholesterol.8 The current report from Iribarren et al9 in this issue of Circulation attempts to make this distinction in an effort to determine prospectively whether having a low serum cholesterol level is hazardous to health. Iribarren et al9 go beyond the usual classification of low cholesterol based on a single measure and instead have examined future disease risk according to whether cholesterol level was stable over about 6 years or whether low cholesterol resulted from falling blood cholesterol levels. Among nearly 6000 healthy Japanese-American men enrolled in the Honolulu Heart Study, they measured total serum cholesterol at two time points, with mortality follow-up extending for up to 16 years. Results showed the expected association of elevated cholesterol with coronary disease. In addition, falling levels of cholesterol were linked to an excess risk of hepatic disease and cancer in particular, whereas low (<4.7 mmol/L, <180 mg/dL) but stable levels over time were not associated with excess risk. Their findings provide evidence that the association previously reported between low cholesterol and noncoronary mortality probably reflected the cholesterol-lowering metabolic consequences of long-term subclinical disease rather than a hazard associated with low cholesterol per se. This conclusion is consistent with results of a recent meta-analysis10 of causespecific mortality (including unpublished data on noncardiovascular causes of death) from 10 large cohort studies and 2 international studies that concluded that reduced serum cholesterol is not related to excess mortality among cohorts of employed individuals, whereas population-based studies did show a relationship. The investigators proposed that the discrepancy in results was probably due to a higher frequency of risk factors associated with low cholesterol, eg, alcohol abuse and ill health, in population-based study samples compared with employed cohorts. Two additional pieces of evidence that suggest that low cholesterol is not a
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causal factor for noncardiovascular disease are the normal to extended life expectancy experienced by individuals with genetically determined hypobetacholesterolemia11 and populations with low average blood cholesterol levels, such as the Japanese and Greeks, who do not exhibit an excess of noncardiovascular disease deaths.12 One strength of the investigation by Iribarren et al9 is its ability (albeit limited to two measures) to track cholesterol over time. In an effort to eliminate the possible cholesterol-lowering effects of latent disease, previous studies have excluded from analyses deaths within the first 2, 5, or 10 years of follow-up. The results found by Iribarren et al7 suggest that a drop in serum cholesterol may occur over a decade before disease is diagnosed. This is plausible; at least two examples of long-term morbidity leading to cholesterol reduction are hepatitis B virus infection13 and chronic respiratory disease resulting in repeated respiratory infections.14 A limitation of the study by Iribarren et al9 is the exclusion of women from the study population. The dearth of information on the effects of low cholesterol and cholesterol lowering in women and children is one rationale for not supporting population-based efforts to reduce cholesterol levels.3 This issue remains unresolved, although the association between low cholesterol and disease appears to be much weaker for women than for men.1 A further limitation of the present report6 is the relatively small number of subjects with sustained low-cholesterol level (n=376), reflecting the generally elevated serum cholesterol level among westernized populations. The ability to detect any but large increases in risk of disease is limited by the size of the group exposed to persistent low cholesterol. Finally, it is important to note that the study by Iribarren et al9 was not designed to address the issue of whether cholesterol-lowering treatment is associated with excess risk of noncoronary deaths. In particular, cholesterollowering treatment has been related to an excess of violent deaths, including suicide.15 It is important to recognize that individuals with serum cholesterol sufficiently elevated to require drug or diet therapy are certainly a different group altogether from individuals with low cholesterol caused by lifestyle or genetic factors. Moreover, a reduction in cholesterol from 240 mg/dL or higher, even by as much as 20%, does not result in a low serum cholesterol level. The
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present report9 did not distinguish individuals with a reduction in cholesterol resulting from treatment for hypercholesterolemia from those with a spontaneous drop. Thus, the current findings reported by Iribarren et al9 cannot be related directly to clinical trials of reduction of hypercholesterolemia. The public health significance of the report by Iribarren et al is the evidence it provides that population-based recommendations for lowering cholesterol levels will not lead to adverse health consequences. They conclude that the reported association of low cholesterol levels with increased mortality is probably due to cholesterol-lowering effects of existing disease. Their results offer reassurance for individuals with naturally occurring low cholesterol levels and support for the notion that national guidelines to reduce cholesterol are consistent with public health interests.

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. Copyright 1995 by American Heart Association

References

1. Jacobs DR, Blackburn H, Higgins M, Reed D, Iso H, McMillan G, et al. Report of the conference on low blood cholesterol: mortality associations. Circulation . 1992;86:1046-1060. Abstract/FREE Full Text [2] 2. Frank JW, Reed DM, Grove JS, Benfante R. Will lowering population levels of serum cholesterol affect total mortality? Expectations from the Honolulu Heart Program. J Clin Epidemiol.. 1992;45:333-346. 3. Hulley SB, Walsh JMB, Newman TB. Health policy on blood cholesterol: time to change direction. Circulation . 1992;86:1026-1029. Editorial.

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FREE Full Text [3] 4. Glatz JFC, Turner PR, Katan MB, Stalenhoef AFH, Lewis B. Hypo- and hyperresponse of serum cholesterol level and low density lipoprotein production and degradation to dietary cholesterol in man. Ann N Y Acad Sci.. 1993;676:163-179. Medline [4] 5. Hyman DJ, Barrett DC, Fortmann SP. Effect of minor illness on serum cholesterol level. Am J Prev Med. 1992;45:595-601. 6. Rose G, Shipley MJ. Plasma lipids and mortality: a source of error. Lancet. 1980;523-526. 7. Iribarren C, Dwyer JH, Buchfiel CM, Reed DM. Can the U-shaped relation between mortality and serum cholesterol be explained by confounding? Circulation. 1993;87(suppl 2):7. Abstract. 8. Meilahn EN, Ferrell RE. Naturally occurring low blood cholesterol and excess mortality. Coron Artery Dis.. 1993;4:843-853. Medline [5] 9. Iribarren C, Reed DM, Chen R, Yano K, Dwyer JH. Low cholesterol and mortality: which is the cause and which is the effect? Circulation . 1995;92:2396-2403. Abstract/FREE Full Text [6] 10. Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. BMJ.. 1994;308:373-379. Abstract/FREE Full Text [7] 11. Glueck CJ, Gartside P, Fallat RW, Sielski J, Steiner PM. Longevity syndromes: familial hypobeta- and familial hyperalpha-lipoproteinemia. J Lab Clin Med..
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1976;88:941-957. Medline [8] 12. Kromhout D, Katan MB, Menotti A, Keys A, Bloemberg B. Serum cholesterol and long-term death rates from suicide, accidents, or violence. Lancet.. 1992;340:317. Letter. 13. Chen Z, Peto R, Collins R, MacMahon S, Lu JR, Li WX. Serum cholesterol concentration and coronary heart disease in populations with low cholesterol concentrations. BMJ.. 1993;303:276-282. 14. Kerttula Y, Weber T. Serum lipids in pneumonia of different aetiology. Ann Clin Res.. 1988;20:184-188. Medline [9] 15. Muldoon MF, Manuck SB, Matthews KA. Lowering cholesterol concentrations and mortality: a quantitative review of primary prevention trials. BMJ. 1990;301:309-314.

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