There is no doubt that the present notoriety of cholesterol has all but obscured its physiological importance and necessity in our bodies. Cholesterol is not only the most common organic molecule in the brain, it is also distributed intimately throughout the entire body.
It is an essential constituent of the membrane surrounding every cell. The presence of cholesterol in this fatty double layer of the cell wall adjusts the fluid level and rigidity of this membrane to the proper value for both cell stability and function.
Additionally, cholesterol is metabolized into other essential body steroids known as the steroid hormones and is therefore the sole source for the formation of the very powerful chemicals in our body that determine our sexuality, control the reproductive process and make possible our very existence (1).In its misguided war on cholesterol as the primary cause of atherosclerosis, the pharmaceutical industry would lead us to believe that a rapid bottoming out of our natural cholesterol levels through the use of statin drugs is a relatively innocuous process of definite benefit to society. But as we learn more each day of this ubiquitous and unique cholesterol substance, we must question the veracity of this advice. Cholesterol is perhaps the most important substance in our lives.
In the past 30 year quest for ever more powerful cholesterol busting drugs, the development of statin drugs by the pharmaceutical industry was an almost inevitable phenomenon. When two molecules of HMG-CoA combine to form the ubiquitous mevalonic acid, the enzyme, HMG-CoA reductase is required.
This enzyme could quite easily be inhibited and suddenly a multi-billion dollar industry was born with the development of the HMG-CoA reductase inhibitors known as the statin drugs (2). Whether Lipitor, Mevacor, Zocor, Pravachol, Crestor or the ill-fated Baycol, all use the same mechanism and are merely variations of the same theme as developed by different pharmaceutical companies.
Statin drugs, while curtailing cholesterol, must inevitably inhibit the production of other vital intermediary products that originate further down the metabolic pathway beyond the statin blockade (3,4,5,6,7). The pharmaceutical industry has long been attempting to develop a means by which interference with cholesterol production might be achieved beyond the point where these vital intermediary products originate (8) but up to now have failed. The inevitability of significant, serious and even lethal side effects has been knowingly accepted.
The side effect profiles that have resulted from statin drug use can be grouped into those associated with excessive impairment of cholesterol biosynthesis, those associated with collateral damage to other substances along the vital mevalonate pathway and those associated with nuclear factor kappa B inhibition (9), the very process by which statin drugs appear to exert their benefit.
Side Effects Associated with Excessive Interference with Cholesterol Bioavailablity.
The following personal account by the author has now been replayed hundreds of times in emergency rooms throughout the world as statin users are seen for their amnesias. His was one of the first statin associated transient global amnesia (TGA) cases reported to the UCSD statin study four years ago.My personal introduction to the incredible world of TGA occurred six weeks after Lipitor® was started during my annual astronaut physical at Johnson Space Center.
My cholesterol had been trending upward for several years and all was well until six weeks later when my wife found me aimlessly walking about the yard after I returned from my usual walk in the woods.
I did not recognize her, reluctantly accepted cookies and milk and refused to go into my now unfamiliar home. I "awoke" six hours later in the office of the examining neurologist with the diagnosis of transient global amnesia, cause unknown. My MRI several days later was normal. Since Lipitor was the only new medicine I was on, the doctor in me made me suspect a possible side effect of this drug and, despite the protestations of the examining doctors that statin drugs did not do this, I stopped my Lipitor.
The year passed uneventfully and soon it was time for my next astronaut physical. NASA doctors joined the chorus I had come to expect from physicians and pharmacists during the preceding year, that statin drugs did not do this and at their bidding I reluctantly restarted Lipitor at one-half the previous dose.
Six weeks later I again descended into the black pit of amnesia, this time for twelve hours and with a retrograde loss of memory back to my high school days. During that terrible interval, when my entire adult life had been eradicated, I had no awareness of my marriage and children, my medical school days, my ten adventure-filled years as a USAF flight surgeon or my selection as NASA scientist astronaut.
All had vanished from my mind as completely as if they had never happened. Fortunately, and typically for this obscure condition, my memory returned spontaneously and again I drove home listening to my wife's amazing tale of how my day (and hers) had gone."
Transient global amnesia is the sudden inability to formulate new memory, known as anterograde amnesia, combined with varying degrees of retrograde memory loss, sometimes for decades into the past(9).
Until recently, the most common trigger events for these abrupt and completely unheralded amnesia cases have been sudden vigorous exercise, sex, emotional crises, cold water immersion, trauma--at times quite subtle, and cerebral angiography. In the past four years a new trigger agent has been added - the use of the stronger statin drugs.
Probable explanation for statin drugs' effect on cognition was to come on 9 November 2001, when Dr. Pfreiger of the Max Planck Society for the Advancement of Science announced to the world the discovery of the identity of the elusive synaptogenic factor responsible for the development of the highly specialized contact sites between adjacent neurons in the brain known as synapses(11,12). Not surprisingly to specialists in the field, the synaptogenic factor was shown to be the notorious substance cholesterol!
The so-called glial cells of the brain, long suspected of providing certain housekeeping functions, were shown to produce their own supply of cholesterol for the specific purpose of providing nerve cells with this vital synaptic component. Since the lipoproteins that mediate the transport of cholesterol, including both LDL and HDL, are too large to pass the blood-brain barrier, the brain cannot tap the cholesterol supply in the blood(13). The brain must depend upon its own cholesterol synthesis, which the glial cells provide. The highly lipophilic statin drugs more easily cross the blood/brain barrier and interfere directly with glial cell synthesis of cholesterol.
Side Effects Associated with the Collateral Damage of Statin Drugs
Ubiquinone is arguably our most important essential nutrient (14). Its role in energy production is to make possible the transfer of electrons from one protein complex to another within the inner membrane of the mitochondria to its ultimate recipient, ATP.
The adult human body pool of this substance has been reported to be 2 grams and requires replacement of about 0.5 gms per day(15). This must be supplied by endogenous synthesis or dietary intake. Synthesis decreases progressively in humans above age 21, and the average ubiquinone content of the western diet is less than 5 mg/day.
Thus, ubiquinone supplementation appears to be the only way for older people to obtain their daily need of this important nutrient. Nearly 40 million people will be taking Lipitor this year in the United States alone with an additional 20 million taking other types of statin drugs of comparable effect. Most of these people will be over 50 years of age.
Few of them will be on supplemental ubiquinone. Simple logic dictates that the statin drug impact on ubiquinone availability and mitochondrial energy production will be profound. In the June 2004, Archives of Neurology, the Neurology Department of Columbia University reported a greater than 50% fall in plasma Coenzyme Q10 (ubiquinone) in their group taking Lipitor 80 mg for 30 days, in a striking documentation of the impact of statin therapy on ubiquinone biosynthesis.
The importance of mitochondrial function in meeting the energy needs of the heart has been emphasized because of the increasing tendency for congestive heart failure (CHF) in statin drug users (16). Cardiologist Peter Langsjoen has published a series of excellent articles on this subject (17) and reviewed the prevalence of statin associated (CHF) in many controlled studies, reporting on the prompt response of (CHF) to supplemental ubiquinone or substantial reductions in statin dosage.
Although the heart may be the first to show effects of ubiquinone deprivation, every cell and every tissue in the body is equally dependent upon mitochondrial energy supply. Recently the relationship between chronic fatigue and ubiquinone deficiency has been reported (18), a complaint of growing proportions as ever increasing numbers of persons are placed on statin drugs.
In addition to the critically important role of ubiquinone in energy production, it has a possibly even greater role within the mitochondria as an anti-oxidant, with a free radical quenching ability perhaps some 50 times greater than that of vitamin E. Without adequate stores of ubiquinone and lacking the repair mechanisms common to nuclear DNA, irreversible oxidative damage to mitochondria DNA results from buildup of superoxide and hydroxyl radicals (19).
We must remember that our mitochondria are in immediate contact with oxygen, front line warriors so to speak in our struggle to obtain life giving oxygen without sustaining excessive oxidative damage. The inevitable result of excessive free radical accumulation is an increase in the rate of mitochondrial mutations. According to some the cumulative effect of somatic mitochondrial mutations may contribute directly to many chronic myopathies, diabetes and even aging (20).
Ubiquinone in a slightly altered form known as ubiquinol is found in all cellular membranes where it has a vital function in maintaining membrane integrity. Compromise of this important role is thought to be involved in the increasing number of statin associated neuropathies as reported by Gaist (21), as well as the flood of myopathy reports (22) and the frequently fatal form of muscle damage known as rhabdomyolysis.
Although Baycol was recently removed from the market because of its association with excessive deaths from rhabdomyolysis, deaths from this extreme form of muscle cell breakdown still are being reported. The dolichols are another area of collateral damage from statin use. This class of compounds is involved in an intricate process of cellular activity involving message transport(23).
Proteins manufactured there in response to DNA directives are packaged into transport vesicles that are shuttled across the cytoplasm to their various destinations. Without dolichols there would be intracellular chaos as various proteins could not be directed to their proper target and would, in effect, be dead-lettered. The post office analogy, though childishly simple, comes very close to describing dolichol's function as we understand it today.
Since the discovery in 1975 of internally produced opiates, popularly described as Beta endorphins and finally labeled as neuropeptides, legions of scientists have explored the nature and role of these ubiquitous substances (24). The purpose of this paper is not to present a detailed description of neuropeptide physiology but rather to direct reader attention to the potential adverse effects from statin drug use on this system.
Neuropeptides are biochemicals that regulate almost all life processes on a cellular level, thereby linking all body systems (25,26). Although produced primarily in the brain, every tissue in the body produces and exchanges neuropeptides, called messenger molecules, they send chemical messages in the form of linked peptides from the brain to receptor sites on cell membranes throughout the body.
Until recently such intercellular information transfer was felt to be the sole province of classic neurotransmitter chemicals such as serotonin and catecholamines, gate-keepers of the synapses, aided by various hormones carried by the vascular system. Now we have learned that neuropeptides more than supplement these systems, they provide the majority of information transfer (27).
Not only do these protein chains carry information throughout the body, they mysteriously seem to be the information. They do not simply convey thought, sensation or emotion; these peptide clusters are the thought, sensation or emotion in a process we are only just beginning to understand.
Most of us are familiar with the blocking action of statins on ubiquinone but few really understand the consequence of dolichol suppression. Without dolichols the intricate process of neuropeptide formation and transport could not occur.
Side Effects Associated with the Anti-Inflammatory Action of Statins.
Even if the dedicated researchers of the pharmaceutical industry discover a way around the side effect mechanisms already described, even greater hurdles exist from evidence that statins work not by cholesterol manipulation but by some basic anti-inflammatory mechanism (9,28,29,30).
Key to this is a substance known as nuclear factor kappa B. All statins inhibit this vital step in the immune system's ability to defend us from alien forces (31). Whether by being the recipient of a donor kidney or under attack by bacteria or viruses, the immune system has evolved a defensive strategy in which suppression of inflammation, triggered by nuclear factor kappa B, plays a vital role. Such stimulants to inflammation include the foreign by-products of arterial inflammation and damage. Statin drugs are known to suppress this nuclear factor kappa B (NF-kB) response and thereby open a veritable Pandora's box of unpredictable consequences.
At best, HMG Co-A reductase inhibitors are blunt instruments and the immuno-defense system is both delicate and complex. During eons of co-existence of the complex multicellular life forms with competing, simpler unicellular organisms, there have develped many different forms of defensive and offensive strategy - all dealing with the needs of one or the other of these dueling organisms to gain a survival advantage.
We have had 3.5 billion years to work out our defense systems against widely diverse challenges and NF-kB is key to all of them. If we thought the complexity of cholesterol manufacture by the body is complex, it's child's play compared to what is involved in anti-infection and immuno-modulation. Now, throw in a statin and try to predict the consequences.
NF-kB in its several forms is known to molecular biologists as a transcription factor and my bringing more than a smattering of this complex subject to your attention would risk losing you from terminal boredom, so skim the following very lightly. I warned you this is challenging - how could a history of a 3.5 billion year war be otherwise? NF-kB resides in the cytoplasm of each cell in five different forms known to molecular biologists as family.
The offspring of these family members, known as dimers, remain held in check in the cytoplasm by certain inhibitory proteins until a release signal is received, allowing the now activated NF-kB to enter the nucleus of the cell. It is there, in the nucleus, that it completes its mission in life to stimulate genes and manufacture proteins necessary for such diverse tasks as monocyte adhesion, macrophage recruitment, smooth muscle migration and platelet activation, key elements of the defensive inflammatory response.
With so many steps involved, a good strategist could predict many different forms of assault by dedicated viruses, bacteria and other forms of single celled life, for this war is basically that of the monocellular rulers originally dominating life on our planet against we multicellular usurpers.
Therefore it should come as no surprise that some of these defenders have managed to gain an advantage over us, their adversary, by inhibiting NF-kB while others succeed by enhancing NF-kB (32). Others manage both sides of the coin. E. coli, one of the most common infectious agents, prevents NF-kB from entering the nucleus, thereby enabling this ubiquitous organism freer access to bladder walls and urethras.
Through a similar process of checkmate, another common bacteria, Salmonella, inhibits the anti-inflammatory response sufficiently long to allow bacterial colonization of the lining of the gut, giving a decided advantage to "their" side. On the other hand, some Chlamydia organisms, warring against the urogenital systems of both men and women, have evolved a distinct advantage by enhancing NF-kB, thereby assuring increased survival of infected cells in urinary and reproductive systems.
On a far more serious note, the very common Epstein-Barr virus causing infectious mononucleosis uses NF-kB inhibition to help destroy protective "T "cells as part of the common teenage "mono" presentation (33) but when it decides to go on a malignant rampage, triggering nasopharyngeal carcinoma and Burkitt's lymphoma, it does so through sustained NF-kB activation (34). The list goes on and on with other microorganisms and foreign antigens of all kinds, numbering thousands of variations of these basic themes.
So now let us return to statin drugs and their effect of inhibition of NF-kB. What does this really mean in our ancient struggle with disease organisms and our immune system's competence? It means while taking statins we are likely to be far more susceptible to certain common infectious agents but at the same time may be somewhat more resistive to others.
In the case of the Epstein Barr virus, perhaps we will see more "mono" but, fortunately, less nasopharyngeal carcinoma and Burkitt's lymphoma. But the reality is that we do not as yet know because this new statin role of NF-kB inhibition has only just been recognized. The potential for increased risk of both infectious disease and malignancy is there, for both depend upon the immune system's competence.
Tossing the statin sledgehammer into this system is perhaps quite comparable in effect to the rampages of "a bull in a china shop" and it is far too soon to tell about most malignant changes. The implications of the very recent drug company promotion of statin drugs for organ transplant recipients (35,36) and as adjunctive therapy in the treatment of auto-immune diseases (37,38) are sobering, indeed, for these drugs can only work in this capacity at the risk of causing mischief elsewhere.
Increased cancer deaths among recipients of statin drugs already are being observed. Ravnskov (The Cholesterol Myths) has reported of the recent PROSPER trial (39) that statin therapy increased the incidence of cancer deaths, completely offsetting the slight decrease in deaths from cardiovascular disease. As Dr. Paul Rosch predicted in his Weston Price Foundation presentation of May 2003(40), the Japan Lipid Intervention trial observed excess deaths from malignancy in their so-called statin "hyper-responder" group (41). Of the 12 cancer deaths reported in this group whose cholesterol plummeted deeply with statin use, four were from gastric cancer and two were from lung cancer. Although other factors may have played a role, this heightened cancer risk may well be based on loss of immuno-resistance secondary to NF-kB inhibition.
How strange it is that a class of drugs developed solely for the purpose to interfering with the biosynthesis of cholesterol has now been shown to reduce cardiovascular risk by an anti-inflammatory role completely unrelated to cholesterol manipulation. Generally speaking this should by a welcome observation, for atherosclerosis with all of its consequences is based primarily upon inflammation within the arterial walls. Now, however, any optimism we might have had is thoroughly tempered by the growing realization that statins' effect is probably based upon interference with the most basic immuno defense system. The potential consequences are frightening.
The side effects we are seeing from the statin class of drugs are extraordinarily diverse reflecting a multiplicity of causes. From lack of sufficient bio-availability of cholesterol to excessive inhibition of the ubiquinones and dolichols sharing the mevalonate pathway to the consequences of the newly recognized anti-iflammatory action of statins, the opportunity for serious side effects are legion.
One must ask if the ever increasing use of statin drugs is cost-effective? Yes, we are unquestionably reducing cardiovascular risk with statin use but having learned that atherosclerosis is probably an inflammatory disease based on McCully's (42) homocysteine (The Homocysteine Revolution) and other non-cholesterol "trigger factors" the focus should, I believe, be on inflammation reduction. Many safe and readily available supplements have been shown to have very substantial anti-inflammatory benefits. Omega 3, coenzyme Q10 and other anti-oxidants, vitamins B6,12 and folic acid and buffered aspirin all have been shown to favorably impact the inflammatory process (43,44,45).
Surprisingly, we are discovering that the 40-year war on cholesterol through the use of drugs and the now infamous low fat/low cholesterol diet seems to have been grossly misdirected. We have become a nation of fattened sheep, prone to type 2 diabetes and with unchanged proneness to arteriosclerosis. Despite the mounting evidence for cholesterol's irrelevance and the growing belief of inflammation as the basis of atherosclerosis, the public still remains desperately focused on cholesterol.
1. Guyton AC, Hall JE. The adrenocortical hormones. In Textbook of Medical Physiology, 5th Ed, 957-971, Saunders, Philadelphia, 1996
2. Gotto AM Jr. Cholesterol management in theory and in practice. Circ. 96; 4424-30, 1997
3.Bliznakov EG, Wilkins DJ. Biochemical and clinical consequences of inhibiting coenzyme Q10 biosynthesis by lipid-lowering HMG-CoA reductase inhibitors (statins). A critical review. Adv Ther. 15(4); 218-28, 1998
4. Griffiths G, Simons K. The trans-Golgi network: Sorting the exit side of the Golgi apparatus. Science 243; 438-42, 1986 5.Bargossi AM and others. Exogenous CoQ10 supplementation prevents ubiquinone reduction induced by HMG- CoA reductase inhibitors. Mol Aspects Med. 15(Suppl); S187-93, 1994
6. De Pinieux and others. Lipid-lowering drugs and mitochondrial
function: effects of HMG-CoA reductase inhibtors on serum ubiquinone and blood lactate/pyruvate ratio. Br J Clin Pharmacol. 42(3); 333-37, 1996
7. Folkers K and others. Lovastatin decreases coenzyme Q levels in humans. Proc Natl Acad Sci USA. 87(22); 8931-34, 1990
8. Whitaker J. Citizens' petition filed with FDA to include Coenzyme Q10 use recommendation in all statin drug labelling. Life Extension Magazine, May 23, 2002
9. Hodges JR, Warlow CP. The aetiology of transient global amnesia: A case-control study of 114 cases with prospective follow-up. Brain 113; 639-57, 1990
10. Golomb B and ohers. Amnesia in association with statin use. UCSD College of Medicine, Statin Research Study, (in process) 2004
11. Pfrieger F. Brain researcher discovers bright side of ill-famed molecule. Science. 9 November, 2001
12. Pfrieger F. Cholesterol homeostasis and function in neurons in the central nervous system. Cell Mol Life Sci 60; 1158-71, 2003
13. Brousseau ME, Schaefer EJ. "Structure and mechanism of action of HMG-CoA reductase inhibitors" in HMG-CoA Reductase Inhibitors. Schmitz G, Torzewski M, Eds, Basel, Schweiz, Birkhauser, 2002
14. Ely JTA, Krone CA. A brief update on ubiquinone (Coenzyme Q10 ). J Orthomol Med 15(2); 63-8, 2000
15. Ely JTA, Krone CA. Urgent update on Ubiquinone (Coenzyme Q10). (www.faculty.washington.edu/ely/turnover.html), 2000
16. Langsjoen P, Langsjoen A. Statin associated congestive heart failure. Proceedings of Weston-Price Foundation meeting, Spring 2003
17. Langsjoen P, Langsjoen A. Co-enzyme Q10 in cardiovascular disease with emphasis on heart failure and myocardial ischemia. Asia Pacific Heart J 7(3); 160-8, 1998
18. Chronic fatigue, aging, mitochondrial function and nutritional supplements. The Townsend Letter, 2003
19. Dean W, Fowkes SW. Mitochondrial nutrition, aging and cognition. (www.ceri.com/mito.htm), August 1996
20. Wallace DC. Mitochondrial DNA in aging and disease, Sci Amer; 40-7, August 1997
21. Gaist D and others. Statins and the risk of polyneuropathy: A case-control study. Neuro 58;1333-37, 2002
22. Phillip PS and others. Statin-associated myopathy with normal creatine kinase levels. Ann Int Med 137(7); 581-85, 2002
23. Griffith G, Simons K. The trans-Golgi network: Sorting out the exit side of the Golgi complex. Science 242; 438-42, 1986
24. Pert C. Molecules of Emotion, Scribner, New York, 1997
25. Lambrecht BN. Immunologists getting nervous: neuropeptides, dendritic cells and T cell acivation. Resp Research 2;133-38, 2001
26. Norris JF and others. Neurosecretion: Retrospectives and Perspectives. HW Korf and KH Usadel, Eds. Springer, Berlin, 71-85, 1997
27. Hokfelt T and others. General overview of neuropeptides. The fourth generation of progress. (www.acnp.org/g4GN401000047/CH.html), 2000
28. Shovman O and others. Anti-inflammatory and immunomodulatory properties of statins.
10 December 2001
29. Hilgendorff A and others. Statins differ in their ability to block NF-kB activation in human blood monocytes. Internat J Clin Pharm and Therapeut 41(9); 397-401, 2003
30. Karin M, Delhase M. The 1 kappa B kinase and NF-kappa B: key elements of proinflammatory signaling. Semin Immunol 12(1); 85-98, 2000
31. Masato E and others. Statins prevent tissue factor expression in human endothelial cells. Circ 103; 1736, 2002
32. Tato CM, Hunter CM. Host-pathogen interactions: subversion and utilization of the NF-kB pathway during infection. Infect and Immun 70(7); 3311-17, 2002
33. Atkinson PGP and others. Latent membrane protein 1 of Epstein-Barr virus stimulates processing of NF-kB p100 to p52. J Biol Chem 278(51); 51134-42, 2003
34. Thornburg NJ and others. Activation of nuclear factor-kB p50 homodimer/Bci=3 complexes in nasopharyngeal carcinoma. Cancer Research 63; 8293-8301, 2003
35. Raggat LJ, Partridge NC. HMG-CoA reductase inhibitors as
immunomodulators: potential use in transplant rejection. Drugs 62(15); 2183-91, 2002
36. Kwak B and others. Statins as a newly recognized type of immunomodulator. Nature Med 6; 1399-1402, 2000
37. Leung BP and others. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. J Immunol 170(3); 1324-30, 2003
38. Palinski W. Immunomodulation: A new role for statins? Nature Med 6; 1311-12, 2000
39, Ravnskov U. The Cholesterol Myths. New Trends Publishing, 2000
40. Roach, P. Increased cancer risk associated with statin drug use. Proceedings of the Weston-Price Foundation Meeting. Spring, 2003
41. Matsuzaki, M and others. Primary prevention Cohort Study of the Japan Lipid Intervention Trial (J-LIT). Circ J 66; 1087-95, 2002 42. McCully KS. The Homocysteine Revolution. Keats, 1997
43. Fallon S, Enig M. What causes heart disease? Lancet 1;1062-83, 1983
44. Kauffman J. Should you take aspirin to prevent heart attack? J. Sci Explor 14(4); 623-41, 2000
45. Vos E. Nutrition, health and heart disease. (www.health-heart.org)
Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor