The Statin-Low Chol...
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The Statin-Low Cholesterol-Cancer Conundrum

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Hundreds of millions of people all over the globe are currently being administered statins because it is believed that their lipid lowering actions provide cardioprotective benefits. Adverse effects are considered uncommon and mild, and authors of numerous case–control studies of patients on statin treatment and matched, untreated individuals have even suggested a protective effect against numerous non-cardiovascular diseases, including cancer. In contrast, four controlled, randomized statin trials have resulted in a statistically significant increase of cancer in the treatment group; and several case–control and cohort studies have also shown a significant risk of cancer associated with statins. To add further confusion to this issue, meta-analyses of controlled, randomized statin trials have shown neither an increased nor a decreased risk of cancer.1 Some of these discrepancies may result from the failure to recognize that the recordings of cancer in statin trials are biased for several reasons.

Possible mechanisms of action and the role of lipoproteins

There are several possible mechanisms behind the inverse association between cholesterol and cancer. Either the statins are carcinogenic by themselves, or low cholesterol resulting from statin therapy may weaken the body's defenses against cancer, or unknown factors may be carcinogenic and at the same time lower cholesterol.

The first possibility is utterly complicated, because unlike the vast majority of known carcinogens, the statins are neither mutagenic nor genotoxic.23 If they are carcinogenic, the reason may be their disruption of immune system function, for instance by increasing the number of regulatory T cells.26 Another possibility is that the statins may enhance the genotoxicity of other substances.27 However, arguments have also been presented in favor of a cancer-protective effect.28 This is obviously a difficult problem to study because of the many biochemical pathways that are blocked by the statins. We have abstained from analyzing this issue because of its complexity and because these ideas are speculative and are based solely on laboratory experiments.

The arguments in favor of the second possibility, that low cholesterol may increase risk, are more compelling, and are also supported by human studies. The strongest argument is the collection of cohort studies listed in Table 1, all of which were started before cholesterol-lowering treatment became popular. Also other studies indicate that low cholesterol, or rather a low concentration of the lipoproteins, may be crucial.

More than 50 years ago several research groups found that carcinogenic hydrocarbons are rapidly bound by lipoproteins29 suggesting that cells of people with high blood cholesterol may have less exposure to carcinogens and thus be protected against cancer. But the lipoproteins may protect in another way. 

One hundred years ago Ellermann and Bang succeeded in transferring leukemia from one chicken to another by cell-free tissue filtrates, and shortly thereafter Peyton Rous isolated the sarcoma virus of hens. More recently, compelling links have been found between human papilloma virus and cervical cancer, between Epstein–Barr virus and Burkitt's lymphoma, between T-cell leukemia virus and lymphoma and between hepatitis B-virus and liver cancer.30 It has been estimated that 15–20% of human cancers may have a viral etiology, and there is increasing evidence that certain bacteria may play a similar role.31 These findings are crucial because the lipoproteins partake in the immune defense system by binding and inactivating microorganisms and their toxic products.32,33

In 1939, Todd et al. discovered that a serum factor named antistreptolysin-S was not an antibody, as previously thought, because its titer fell in patients with rheumatic fever at the peak of clinical symptoms. Humphrey localized it to the lipid fraction of the blood, and since then more than a dozen research groups have documented that antistreptolysin-S is identical with the lipoproteins and constitutes a non-specific host defense system able to bind and neutralize not only streptolysin-S, but also other endotoxins and a large number of bacteria and virus species.32 For instance, test tube studies have shown that human low density lipoprotein (LDL) inactivates up to 90% of Staphylococcus aureus alpha-toxin, and an even larger fraction of bacterial lipopolysaccharide (LPS).32 In accordance, hypocholesterolemic rats injected with LPS had a markedly increased mortality compared with normal rats, which could be ameliorated by injecting purified human LDL; and hypercholesterolemic mice challenged with LPS or live bacteria had an 8-fold increase of LD50 compared with normal mice.32 Superti et al. confirmed that all human subclasses of lipoproteins were able to inhibit the infectivity and hemagglutination by SA-11 rotavirus, and complex formation was visualized by electron microscopy.32

It has been shown that apolipoprotein B, the primary lipoprotein of LDL and very-low-density-lipoprotein (VLDL) performs an innate defense effector against Staphylococcus aureus infections in mice,34 but there may be other mechanisms as well, because several studies have shown that also HDL partake in the immune defense system.32

There are many clinical observations relating lipoproteins to infectious diseases. Low cholesterol is associated with respiratory and gastrointestinal disease, most of which have an infectious origin, and low cholesterol is also a risk factor for HIV, AIDS, mortality due to postoperative abdominal infections, and sepsis.35 These associations have also been explained with the argument that low cholesterol is secondary to the infection. However, when Iribarren et al.36 followed more than 100 000 healthy individuals for 15 years, they found that those who had low cholesterol at the start had significantly more hospital admissions due to an infectious disease.36 Obviously, the low cholesterol, which was recorded at a time when these people were healthy, could not have been caused by a disease that they had not yet encountered.

The role played by the lipoproteins in innate immunity is in accordance with the findings of Sijbrands et al.37 They tracked the ancestors of Dutch people with familial hypercholesterolemia and identified a large number of individuals with a 50% chance of having this genetic abnormality. They searched official records of deaths and found that before the year 1900 the presumed heterozygotes for hypercholesterolemia lived longer than the average Dutchman. At that time, the most common cause of death was infectious disease. The authors therefore suggested that high cholesterol protected against infections. As some cancers are caused by microorganisms, high cholesterol may protect people with familial hypercholesterolemia against cancer as well. Support for this idea comes from a cohort study by Neil et al.38 of 2871 patients with familial hypercholesterolemia recruited between 1980 and 1998. Their standardized mortality ratio for cancer, calculated from the ratio of the number of deaths observed to the number expected in the general population of England and Wales, was significantly lower (0.6, 95% CI 0.4–0.8).38 The authors suggested that the cause was cholesterol-lowering treatment together with a more healthy lifestyle. Considering that no controlled, randomized cholesterol-lowering trial has succeeded in lowering cancer morbidity or mortality, neither by diet nor drugs, it seems more likely that the lower cancer mortality rates in these individuals resulted from the protection afforded by their high cholesterol.

All lipoproteins are able to neutralize the effects of micro-organisms31,32 and may therefore be carcinoprotective. For instance, several cohort and case–control studies have found that low high-density-lipoprotein cholesterol (HDL-C) is associated with future cancer, especially liver, lung and breast cancer. A meta-analysis of 24 statin trials, in which baseline HDL-cholesterol had been recorded, also showed a strong and significant inverse relationship between baseline HDL-C and the rate of incident cancer.39

Benn et al.40 recently reported that people with genetically low LDL-cholesterol do not have an increased risk of cancer, and they therefore assumed that the association between cancer and cholesterol was secondary. However, information was neither provided about the number of people whose low LDL-cholesterol was inherited nor concerning the particle size of LDL-cholesterol. LDL-particles vary in size; a high number of the small particles, but not of the large ones, is a risk marker for cardiovascular disease, suggesting that small and large particles may have different functions. There is also good reason to suspect that the large particles are more effective both as transporters of toxic compounds and as participants in immune system activities.

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