The world is bracing itself for the coming winter onslaught of the swine flu. While most people who succumb will find it no different in symptoms and severity from other bouts with the flu, some whose resistance is weak will develop complications like pneumonia, which will progress to septic shock, multiple organ failure, and death. Compared to past flu seasons, children will be over-represented among those who die of swine flu, because most of the elderly have antibodies due to previous exposure to H1N1 virus that was widespread before 1956.
Through observation of those who end up in the emergency room with swine flu, it has become apparent that morbid obesity is a strong risk factor (Obesity and Swine Flu) . In Japan, only 1.6% of adults are obese. Correspondingly, in over 2,000 confirmed cases of swine flu, none of the victims died or even became severely ill. In Manitoba, Canada, 60% of the patients who showed up in intensive care units were obese. Similar observations of a correlation with obesity and flu complications have been reported from cities around the world, including Glasgow, Melbourne, Santiago, and New York City.
Since the United States is in the midst of a childhood obesity epidemic, it stands to reason that, among the nations of the world, children in the United States will be among the hardest hit by the coming flu epidemic. Exactly why obesity is a risk factor is not clear. Suggestions have been made that excess fatty tissue may compress the chest and make breathing difficult, or that the obese are physically out of shape and therefore have less efficient lungs, or that insulin resistance may leave them vulnerable to septic shock due to excess sugar in the blood.
The United States is also facing an epidemic in childhood vitamin D deficiency. An article that just appeared in the journal Pediatrics [9] claims that 7 out of every 10 children in the U.S. have vitamin D levels that are too low. Vitamin D deficiency -- a level below the bottom of the normal range -- was observed in 1 out of every ten children. This is a serious condition that can lead to severe problems with bone development, as well as many other negative consequences, related to both the immune system and brain development.
Vitamin D has been shown to provide protection from the flu [4] (Vitamin D Protects from Flu) . In a study involving 19,000 people, it was discovered that people with vitamin D deficiency were 36% more likely to catch the flu, and if they also had asthma their increased risk was five-fold. Vitamin D deficiency is also a clear risk factor for sepsis [7], otherwise known as blood poisoning, which is often the final blow when the disease process advances from flu to pneumonia and subsequent multiple organ failure.
Intriguingly, there is a strong connection between obesity and vitamin D deficiency. Many studies have confirmed that the morbidly obese often have extremely low levels of vitamin D in their blood [1][2]. So children who are obese are more likely to respond badly to the flu, but also more likely to get it, due to their vitamin D deficiency. In fact, I believe that their vitamin D deficiency is the main factor that puts them at greater risk of dying.
Thus, America has been put in a double-jeopardy situation, with simultaneous vitamin D deficiency and obesity epidemics. If we can get at the underlying cause, then we can begin to turn around this trend and greatly improve the long-term health prognosis of our nation's children. I believe that some answers can be found by studying fat metabolism and the critical roles played by vitamin D and calcium.
Before reading further, I would suggest that you take a look at this article that appeared in the Washington Post in 2004 (Active Life of Fat Cells) . I will begin by quoting from their introduction:
"For decades, scientists thought fat cells were passive blobs that did nothing more than store energy, bloat flabby hips and bellies, and perhaps wear down the body by forcing it to cart around a lot of extra weight.
But as the nation's obesity crisis has intensified scientific interest in fat, researchers have fundamentally altered that view: Fat cells, they now realize, are extraordinarily dynamic, complex and influential entities that affect a staggering array of crucial bodily functions."
Fat is now referred to by scientists as a third "endocrine organ:" it releases a complex array of hormones and proteins that, together with hormones released by the thyroid and adrenal glands, orchestrate many body functions. Fat cells dispatch chemical signals to many other organs of the body, including the brain, liver, muscles, reproductive organs and the immune system.
Below, I will develop an argument that obesity is in many cases a consequence of the excessive need for fat cells to store critical nutrients that are inadequately supplied through nutrition. The fat cells themselves release signals that are transmitted through the blood to the appetite control center to cause the person to overeat. One of the critical deficient nutrients is fat itself, but the body is able to manufacture fat from sugar, so excess carbs in the diet can be converted to fats and stored on the body. The fat cells can then release their fat stores whenever there is a need -- for example at night when the body switches over to a fat-metabolism mode and uses the fat to grow new neural pathways or reinforce old ones in the brain. When there is a deficiency in calcium and vitamin D as well, the fat cells' ability to release their fat stores is greatly impaired. Since the delivery rate for each fat cell is significantly lower than would be the case if these two nutrients were sufficient, more fat cells are needed to achieve the same supply rate.
If I am right, then the good news is that two simple lifestyle changes could lead to a significant reduction in both obesity and vitamin D deficiency. The first would be to throw away all soft drinks and replace them with whole milk. The second is to spend more time outside, notably without sunscreen protection.
Soft drinks promote obesity because they provide no nutrients except dissolved sugar, which is digested very quickly causing insulin levels to shoot up. Even diet soft drinks are not the answer. Surprisingly, they also induce weight gain: it is hypothesized that the sweet taste fools the body into expecting sugar, and insulin is released anyway even though the drink contains nothing to digest. (Diet Soft Drinks and Weight Gain) . The overabundance of insulin increases appetite and the child subsequently overeats.
Whole milk, on the other hand, provides three principle ingredients that, in my opinion, are crucial in the fight against both obesity and disease: calcium, vitamin D, and fat. Given today's climate in which fats are much maligned, you may be surprised that I am specifically recommending whole milk as opposed to, for example, nonfat milk. However, the fat in whole milk is at least as important as the vitamin D and the calcium in promoting weight loss. Part of the reason is that the fat is critical to promote the absorption of both vitamin D and calcium [15]. But I will further argue that inadequate fat in the diet may be one of the most significant drivers for our current obesity epidemic, by creating a "fat deficiency syndrome" and consequently programming the body to convert starches to fat and store them in the midrift to provide a steady supply of this essential nutrient, given its dietary insufficiency. Getting fat is a much more significant risk factor to heart disease than eating fat.
Both vitamin D and calcium are much less effective if the other one is deficient. In a careful study of previously published and new studies on the relationship between calcium and vitamin D, Heaney [13] observed that both the blood serum level of vitamin D and the degree to which it is effective both in bone health and in other areas such as cancer protection are dependent upon an adequate supply of calcium in the diet. Furthermore, both of these nutrients are significantly less well absorbed if fat is not available in the gut to promote absorption [15]. Thus these three nutrients all depend on one another to carry out their biological roles. Whole milk (and, more generally, high-fat dairy) provides all three, and hence drinking whole milk is remarkably effective for solving the problem of deficiency in both vitamin D and calcium.
The reason for getting outside is to accumulate as much vitamin D as possible by exposure to the sun, not only because vitamin D plays a crucial role in fighting infection, but also because vitamin D is necessary for efficient metabolism of calcium, and this in turn leads to a reduced need for fat cells. Sun exposure is by far the best way to obtain vitamin D -- it is the preferred method from nature's standpoint, and it assures a good supply of vitamin D in the skin to fight off skin cancer. Just twenty minutes in the sun every day is more than enough exposure to manufacture all the vitamin D you will need. Ironically, the widespread use of sunscreen over the past two decades has led to an increase in the incidence of skin melanoma [10] by about 3% per year since sunscreen usage started to gain popularity in the 1970's. This is in my view directly attributable to the fact that sunscreen with an SPF of 8 or greater completely blocks the body's ability to manufacture vitamin D in the skin, while still not protecting from the very dangerous highest frequency rays of the sun. Vitamin D is nature's version of sunscreen, and it protects against all cancers, not just skin cancer, in addition to its many other roles in maintaining health.
The Complex Interplay among Calcium, Vitamin D, and Fats
Given the American Medical Association's persistent message that Americans should eat as little fat as possible and get as little sun as possible, the consequence is a nationwide epidemic in deficiency of three critical elements: calcium, vitamin D and fat. These three nutrients work together in a coordinated fashion to tightly regulate many biological processes, most notably for our discussion, brain development and the immune system. A consequence that has become very apparent is the alarming increase in brain disorders like Attention Deficient Hyperactivity Disorder (ADHP), Asperger's syndrome, and depression, and corresponding increase in immune system malfunction manifested as allergies, asthma, and perhaps even the rise of Lyme disease.
A hypothesis I propose is that, to try to compensate for a deficiency in all three of these critical nutrients, two distinctly different coping strategies have evolved in America's children, one that tries to store fat on the body and the other that tries to conserve fat depletion in brain development. Both strategies lead to distinctly different but equally dire consequences in terms of health issues. The "silo" strategy is to grow a profusion of fat cells on the body and use them to squirrel away fat, vitamin D and calcium. The fat that's accumulated in the fat cells can be manufactured by the body directly from other food sources. By up-regulating appetite, biological mechanisms signal to the child to eat an excess of the carbohydrates readily available to him. Insulin production goes into high gear, and the carbs are broken down, converted into fat in the liver, and ultimately stored in fat cells dispersed throughout the body, although perhaps concentrated around the midrift. The child then has to cope with all the consequences of metabolic syndrome, including an increased risk to later heart disease and type-II diabetes, as well as a variety of immune system disorders like allergies and asthma. However, at least there is now an on-hand supply of fat readily available to support brain development.
The alternative is to stay thin but conserve the body's fat consumption, for instance, by sacrificing certain aspects of brain development, such as the long-distance pathways necessary for processing external stimuli. This then leads to conditions like Asperger's, where social interaction is seriously impaired, or Attention Deficit Hyperactivity disorder (ADHD), where processes associated with attention are malfunctioning. The myelin sheath that coats the nerve fibers connecting up all the nerve cells in the brain and that is critical for insulating the fibers is made up entirely of fat.
There is a remarkable interplay among calcium, vitamin D, and fats in terms of the ways in which they support one another [6]. Vitamin D acts as a catalyst for calcium transport across membranes. With inadequate vitamin D, calcium is poorly absorbed from foods, so a vitamin D deficient person needs to consume more calcium to achieve the same effect as someone who has enough vitamin D. Vitamin D is very poorly assimilated if taken orally unless it is accompanied by fats. Nature never expected to have to cope with vitamin D in the absence of fat, because it is only found in fatty foods. Fats are responsible for storing vitamin D in the body, and hence they are an important source of it. For example pork lard and butter are both excellent sources. A diet that has eliminated animal fat is essentially a diet without any vitamin D.
Calcium Deficiency Leads to Weight Gain
Quite by accident, it has been discovered that calcium supplements act like a diet pill for obese people and for obese mice alike [12][16][18][19]. During the course of a clinical trial investigating whether calcium would help reduce blood pressure in obese African-Americans [18], it was accidentally discovered that the subjects experienced an unexpected beneficial side effect which was weight loss. After increasing their daily calcium intake by from 400 to 1000 mg/day, over the course of a year, the subjects' body fat was reduced on average by 10.8 pounds.
In a follow-up study of transgenic mice expressing the agouti gene, known to correlate with a predilection to obesity, the mice that were fed a high-calcium diet were found to gain much less weight than the controls, who were fed a high-sugar, high-fat diet. The amount of weight gained by the control group was 39% higher than the amount gained by mice that were fed a high-dairy diet. Mice that were given a high calcium diet but without the dairy were also better off than the controls, but their percentage improvement was only 24%.
These changes were consistent with measures of enzyme expressions that control for fat manufacture and break down. The mice who received calcium had a 51% inhibition of expression of a catalyst for fat synthesis, and a 3.4 to 5.2 fold increase in expression of an enzyme that breaks down fat, compared to the control group. Apoptosis (programmed cell death) of fat cells was also observed; i.e., the number of fat cells went down. These results were all statistically highly significant.
In [17], the authors state, "Dairy sources of calcium exert markedly greater effects which are most likely attributable to additional bioactive compounds in dairy which act synergistically with calcium to attenuate adiposity." "Attenuate adiposity" means "reduce body fat." What might these additional compounds be? I would claim that they are fats! In fact, a study on pre- and peri-menopausal women [15] (Dietary Fat and Calcium Absorption) , which examined the relationship between their ability to absorb calcium in the diet and their dietary habits found that the most significant factor that led to better absorption of calcium was dietary fat, with a highly significant P value of 0.001. A factor that negatively impacted calcium absorption was dietary fiber. So a high-fiber, low-fat diet, probably considered a healthy diet by many people, is particularly bad for calcium absorption. People who were overweight were also less efficient in absorbing calcium than people with a low body mass index. This is likely related to their low vitamin D status, since vitamin D plays an absolutely crucial role in promoting calcium transport.
Why does calcium deficiency lead to weight gain? The answer, according to Zemel, the lead researcher in the above studies, is something that at first seems counter-intuitive. In the presence of calcium deficiency, an increase in the regulatory parathyroid hormone triggers the body to want to horde both vitamin D and calcium in fat cells. Excess amounts of these substances in the fat cells triggers them to reproduce, and also to store additional fat. This in turn increases the appetite, in order to allow more fat to be produced, leading to excess food consumption and weight gain in the form of excess fat. The excess fat is preferentially piled up centrally on the midrift rather than distributed over the limbs. This effect might also partially explain why so many obese people are vitamin D deficient: their body is dumping all the vitamin D that they generate directly into their profusion of fat cells as soon as it is produced, so it is never able to stick around in the blood stream. When the calcium deficiency is corrected through an enrichment in calcium rich foods, the hording process abates, and the number of fat cells is pruned down.
I interpret this very simply to mean that, when there is a deficiency in calcium, the body "decides" to horde it, in order to have it available for critical needs. The only way it knows how to store it effectively is in fat cells, so it needs more of them. I think the same thing applies to both vitamin D and fats as well. So when a person is deficient in all three, they need to have a large quantity of all of them stored in a "silo" around the midrift. When there is a vitamin D deficiency, the efficiency in calcium metabolism is greatly reduced, so even more calcium is needed, for example in bone growth or in fighting infection, than would be the case for someone without vitamin D deficiency.
Vitamin D Deficiency Leads to Weight Gain
While vitamin D is known mostly for its ability to metabolize calcium for strong bones and teeth, it plays a crucial role in many other critical aspects of biology, one of which is associated with regulatiing the amount of fat that is stored on the body. In a DNA microarray study examining which genes are triggered in fat cells by the presence of vitamin D, a total of 93 genes were identified to respond, many of which were associated with the generation and destruction of fat cells [13].
The vitamin D in fat cells influences the efficiency of the fat cells' ability to store and release calcium. And calcium plays a critical role in the storing and releasing of fats. Thus a vitamin D deficient person needs more calcium to get the same level of efficiency from the fat cells as a person who has adequate vitamin D. It stands to reason, then, that increasing the amount of vitamin D available to the fat cell is in some sense equivalent to increasing the amount of calcium, because it improves the ability of the fat cell to use the calcium that it has available.
There is plenty of evidence that vitamin D deficiency is associated with obesity, but this does not necessarily mean that vitamin D deficiency causes obesity. However, a recent study assessing the direct relationship between serum vitamin D levels and weight loss while dieting (Vitamin D Promotes Weight Loss) , found a consistent linear relationship between the amount of vitamin D in the blood and the amount of weight lost -- subjects who had more vitamin D at the start of the study lost more weight. Each 1 ng/mL increase in the vitamin D measure was associated with an additional half pound of weight loss during the diet.
A novel argument for why exposure to the sun may promote weight loss was proposed by Foss [3] in March of this year. It is commonly accepted that there exist control mechanisms which maintain body weight at a set point through homeostatic pathways. These authors state, "Common obesity and the metabolic syndrome may ... result from an anomalous adaptive winter response. The stimulus for the winter response is proposed to be a fall in vitamin D." It has been determined that vitamin D evolved in primitive organisms as a UV-B sensitive photoreceptor which can signal changes in sunlight intensity. When a person wears sunscreen all the time, the body becomes fooled into thinking that they live in a climate with an anomalously weak sun. This implies that they will need to develop a layer of fat to provide insulation from what surely must also be a very cold climate, since in the past a weak sun was always associated with cold weather.
A study done in northern Norway [8], where the sun is very weak and therefore a poor source of vitamin D, looked at the relationship between vitamin D intake from food sources and body mass index. They found a negative association between body mass index and vitamin D, for both men and women, with a highly significant P value (< 0.001). This means that people who were overweight consumed less vitamin D in their diet.
Low Fat Diet leads to Weight Gain
Because it has become common dogma that eating fat makes you fat, I can predict that most obese people in America are arduously avoiding fats in their diet, which, I believe, is the exact opposite of what they should be doing. Children especially need fat, because it is a crucial nutrient for the brain, and children's brains are developing rapidly, growing many new neurons as well as axons and dendrides to connect up all the existing neurons. In my view, an option for children who aren't getting enough fat in their diet is to accumulate a fat supply on their body. Then, fat will be available whenever it is needed for biological functions, most notably, for brain development.
I highly recommend three excellent books that tell a consistent and compelling story about health: fats are good for you; it's the empty carbs that are bad. The book, "Good Calories, Bad Calories," by the New York Times reporter, Gary Taubes [14], shows a slice of bread and butter on the front cover; the message is that the bread is bad and the butter is good. The second book, "Fat and Cholesterol are Good for You," was written by Uffe Ravnskov [11], a Swedish M.D., Ph.D. who has long been obsessed with getting out the message of his book title. The third book is "Trick and Treat", by Barry Groves [5]. This book also argues for a low-carb diet rather than a low-fat diet. However, it also devotes an entire chapter to the subject of vitamin D, which is so intimately associated with animal fats that it becomes unavailable in a fat-free diet. When you compound this with obsessive avoidance of the sun, it's no wonder that Americans are in the throes of a vitamin D deficiency epidemic.
All of these books mention numerous studies in which different groups of people were put on different kinds of diets: high carb diets, high fat diets, and high protein diets. Consistently, the ones on the high carb diets fared the worst, in terms of losing little or no weight, and feeling hungry all the time. The ones on the high fat diet did the best: lost the most weight and felt the least pain doing it.
Conclusion
It is my firm belief that our nation's obsession with low-fat diet and excessive protection from the sun is negatively affecting our children's health in alarming ways. Our children's bodies, in trying to cope with the resulting deficiencies in vitamin D, fats, and calcium, are forced to make tough choices among alternative outcomes that are equally bad but in different ways. They can become obese, in which case there will be enough fat for their brain to develop well, but then they will face all the consequences of metabolic syndrome: increased susceptibility to infection, increased incidence of asthma and allergies, increased risk to heart disease and type II diabetes, etc. The alternative is to stay thin, in which case there will be inadequate fat to supply the brain. Now they will be faced with syndromes like ADHD, Aspergers' and depression, because their brains are starved for fat and can't develop properly.
Those who have opted for the obesity tactic have left themselves extremely vulnerable to the upcoming swine flu epidemic. I predict that America will see a significantly higher percentage of childhood deaths from swine flu than most if not all other nations, due, in my view, to our obsession with low-fat diet and over-protection from the sun.
If we abandon these two widespread practices, our children will become much healthier. With adequate vitamin D, calcium and fat, their brains will develop well, and their bodies can stay thin. Their improved health prognosis will allow them to lead much more productive lives, and will help alleviate our current crisis in health care funding.
References:
[1] Arunabh S, Pollack S, Yeh J, Aloia JF., "Body fat content and 25-hydroxyvitamin D levels in healthy women." J Clin Endocrinol Metab. 2003 Jan;88(1):157-61.
[2] Blum, M., Dawson-Hughes, B., Dolnikowski, G., Seyoum, E., Harris, S.S. "Vitamin D3 in Fat Tissue." Endocrine Journal. 33(1):90-94, 2008.
[3] Foss Y.J.,"Vitamin D deficiency is the cause of common obesity," Med Hypotheses, Mar;72(3):314-21, 2009.
[4] A.A. Ginde, J.M. Mansbach and C. A. Camargok, "Association Between Serum 25-Hydroxyvitamin D Level and Upper Respiratory Tract Infection in the Third National Health and Nutrition Examination Survey," Arch Intern Med. 169: 384-390, 2009.
[5] Barry Groves, Trick and Treat: How 'Healthy Eating' is Making us Ill, Hammersmith Press, 2008.
[6] R.P. Heaney, "Vitamin D and Calcium Interactions: Functional Outcomes," American Journal of Clinical Nutrition, Vol. 88, No. 2, 541S-544S, August 2008.
[7] L. Jeng, A. V Yamshchikov, S.E. Judd. H.M. Blumberg, G.S. Martin, T.R. Ziegler and V.Tangpricha, "Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis," Journal of Translational Medicine, 7:28, April, 2009.
[8] E. Kamycheva, R.M. Joakimsen, and R.Jorde, "Intakes of calcium and vitamin d predict body mass index in the population of Northern Norway," J Nutr. 2003 Jan;133(1):102-6.
[9] Kumar, J. Pediatrics, Vol 124, September 2009.
[10] Lange, J.R. et al., "Melanoma in children and teenagers: An analysis of patients from the National Cancer Data Base." J. Clinical Oncology, 2007 Apr 10; 25:1363-8.
[11] U. Ravnskov, M.D., PhD, Fat and Cholesterol are Good For You,, G. B. Publishing, Sweden, 2009.
[12] Sun, X., Zeme, M.B., "Dietary Calcium regulates Ros prudiction in aP2-agouti transgenic mice on high-fat/high-sucrose diets," Int J. Obes (Lond) 30:1341-1346, 2006.
[13] X. Sun, K. L. Morris and M. B. Zemel. "Role of Calcitriol and Cortisol on Human Adipocyte Proliferation and Oxidative and Inflammatory Stress: A Microarray Study," Nutrigenet Nutrigenomics;1:30-48, 2008
[14] Gary Taubes, Good Calories Bad Calories:Challenging the Conventional Wisdom on Diet, Weight Control, and Disease., Alfred A. Knopf., 2007.
[15] R.L Wolf, J.A Cauley, C.E Baker, R.E. Ferrell, M. Charron, A.W. Caggiula, L.M. Salamone, R.P. Heaney and L.H. Kuller, "Factors associated with calcium absorption efficiency in pre- and perimenopausal women," American Journal of Clinical Nutrition, Vol. 72, No. 2, 466-471, August 2000.
[16] Zemel, M.B., "Calcium and Dairy Modulation of Obesity Risk," Obes. Res. 13:192-193, 2005.
[17] Zemel MB, Miller SL., "Dietary calcium and dairy modulation of adiposity and obesity risk," Nutr Rev. Apr;62(4):125-31, 2004.
[18] Zemel, MB, Richards, J., Milstead, A., Campbell, P, "Effects of Calcium and Dairy on Body Composition and Weight Loss in African-American Adults," Obesity Research 13:1218-1225, 2005.
[19] M.B. Zemel, H. Shi, B. Greer, D. Dirienzo and P. C. Zemel, "Regulation of adiposity by dietary calcium" The FASEB Journal 14:1132-1138, 2000.
Wednesday, August 12, 2009
Wednesday, July 29, 2009
13. Is Atherosclerosis an Infectious Disease?
Atherosclerosis is the technical term for "hardening of the arteries," a process that can eventually culminate in a heart attack. The process starts with an infusion of LDL into the artery wall and ends with a rapid cascade of events leading to plaque rupture and the subsequent release of clotting agents that cause the artery to be completely blocked. As a consequence, the section of the heart supplied by the artery becomes nutrient starved, and it quickly becomes non-functioning and is converted to inert scar tissue. The remainder of the heart then has to work harder to pump blood throughout the body. However, plenty of people survive a minor heart attack and go on living for many years with no obvious disability.
The most clear and unambiguous benefit of statin drugs is that they reduce the incidence of nonfatal heart attacks in men in their 50's. The mechanism by which they achieve this outcome is surely directly tied to their ability to reduce the concentration of LDL in the blood. In careful studies of atherosclerosis, it has been determined that cholesterol in LDL plays a critical role in all stages of the atherosclerotic process. When the supply of LDL is reduced, the entire process is slowed down and the heart attack is delayed or possibly even arrested.
This is surely a good thing? Well, it seems to me that the atherosclerotic process is so intricate and so purposeful that it is hard to believe it plays no role in sustaining health. An excellent and widely referenced article written in 1995 on atherosclerosis [28] provides a fascinating account of all that happens in between the time that the LDL first penetrates the vessel wall and the time of the acute event triggering the heart attack.
Under normal circumstances, the cholesterol enters and leaves the artery wall at the same pace, and no fatty streak accumulates. However, sometimes the LDL "decides" to linger in the wall and also transforms to a weakly oxidized state. This oxidation is a signaling device that encourages white blood cells to join the party. They in turn release chemicals which further oxidize the LDL and trigger an inflammatory response. The newly arrived white blood cells are converted into macrophages, and the LDL, which had been hanging in the extracellular matrix, now take up semi-permanent residence inside the macrophages that are being steadily recruited from the blood supply. Once the LDL becomes highly oxidized it can even become toxic to the macrophages. They release their lipid (fat) droplets which are then consumed by nearby smooth muscle cells lining the artery wall. Over time, the resulting lesion grows outward until it eventually reaches the adventitia, the outermost layer of the artery wall. This situation is deemed a crisis condition, presumably because any further expansion in that direction would penetrate into the heart muscle.
Highly oxidized LDL penetrating all the way to the adventitia triggers a remarkable series of events intent on closing off the artery. High concentrations of "tissue factor" are released from the macrophages, and this tissue factor induces blood clotting by the platelets. The oxidized LDL also inhibits vasodilation, causing the vessel to constrict and furthering the goal of complete closure. Plaque rupture ensues, and more platelets are recruited to the wound site to further encourage a blood clot. In short, systematic biological mechanisms have been preprogrammed to shut down and isolate this segment of the heart.
What could possibly be a good reason to want to kill off a segment of the heart? The article that so beautifully laid out the sequence of events leading to a heart attack never mentioned the idea of an infective agent. However, the entire process would suddenly make sense if you imagine that, when LDL first entered the artery wall, it encountered an infective agent such as a bacterium or a virus, and it was this that triggered it to linger in the artery wall and enter the mildly oxidized state. The macrophages were then recruited to release toxic chemicals with the intent of disabling or even killing the viruses, and then to consume their debris. Meanwhile, the LDL could work on the parallel task of neutralizing toxins released by the infective agents. Further penetration towards the outer wall of the artery was necessitated because the viruses or bacteria were advancing in that direction. Once the enemy reached the outer wall, a crisis ensued because the next step would be penetration of the virus or bacterium into the heart muscle. Such an infection of the heart itself, myocarditis, was something to be avoided at all cost. A minor heart attack, which would essentially turn this segment of the heart into necrotic tissue, would also isolate the infective agent, a preferred outcome to the alternative of letting the infective agent grow unchecked within the heart muscle, leading directly to heart failure.
The notion of heart disease being due to an infective agent was proposed over two decades ago, and is gaining increased traction in recent times. One clear possibility is the extremely common herpes virus, also known as HCMV (Human Cytomegalovirus), which is estimated to infect from 60 to 99 percent of the world's population [3]. Several distinct observations are strongly suggestive of a role played by these viruses [22]. One such observation is that they are capable of triggering many of the steps involved in the above process of atherosclerosis. Another line of evidence comes from a clinical study that showed that patients with high titres of CMV antibodies were at greater risk to atherosclerosis. Direct evidence of their existence in atherosclerotic lesions has been found in the form of HCMV nucleic acids, detected in 90% of the severe atherosclerotic lesions that were examined. A final line of evidence comes from transplant patients --those who tested positive for HCMV infection were at much higher risk to arterial blockage.
A compelling argument for a relationship between an infective agent and atherosclerosis is in the case of children who were infected with typhoid fever. As early as 1911, Klotz and Manning [12] observed that atherosclerosis was particularly pronounced in children who had died from typhoid fever. They concluded that the production of fatty tissue in the arterial wall was the result of a direct irritation of that tissue by the presence of infection or toxins. Many studies have implicated a variety of other common infective agents as being cofactors in causing arterial disease. These include Chlamydia pneumoniae (a common source of pneumonia), Helicobacter pylori (the bacterium that causes stomach ulcers), and HSV and CMV (the one discussed above), both of which cause Herpes [16].
Another indirect argument for the relationship between infection and heart disease is that people who experience an acute heart attack or stroke have disproprortionately just recovered from an infectious disease. These diseases include tuberculosis, sepsis, HIV, chickenpox, tooth infections, and infections of the urinary tract. People with heart disease are encouraged to take steps to prevent gum disease, due to the observed correlation between infections in the gum and atherosclerosis.
A strong proponent of the theory that heart disease is the result of an infective agent is Uffe Ravnskov, a Swedish doctor who has been a tireless advocate of cholesterol as a much-abused and vital biological substance. In his recent book on cholesterol [21], the next-to-last chapter, titled simply "The Real Cause," argues persuasively for the point of view that atherosclerosis is the direct result of infective agents, and also makes a case for LDL's critical role in plaque build-up to protect against the infective agents. Oxidation is the usual way that macrophages destroy bacteria and viruses. Thus the presence of intense oxidation in the plaque is very suggestive of an attempt to neutralize a pathogen. LDL is able to bind and neutralize the alfa-toxin produced by staphylococcus baceteria, and, as we have seen before, it also neutralizes lipopolysccharide, another common bacterial endotoxin. By subsequently changing their structure to induce the macrophages to consume them, the LDL particles effectively render inert the bacteria and their harmful products.
The endotoxins that are released by bacteria are thus clearly implicated in heart disease. Since LDL can bind with and neutralize bacterial endotoxins, one reason why it might settle in the arterial wall, then, is to be available to neutralize the endotoxins of resident bacteria. It has also been shown that bacterial endotoxin stimulates the expression of tissue factor by macrophages (cells that were derived from the white blood cells) [24]. As we have seen from the above discussion on atherosclerosis, tissue factor is probably the single most contributory component for initiating the final cascade in a heart attack. This would presumably occur because the presence of unneutralized endotoxin indicates that the body's defenses have lost the battle against the bacteria at this site. Statins have been shown to inhibit the migration of white blood cells to inflammatory sites [27], which would reduce the bioavailability of tissue factor and therefore possibly prevent the heart attack, but would allow the bacteria and their endotoxin to remain in place and continue to do harm to the surrounding tissues, eventually invading the heart muscle itself.
Thus, the observed rapid rise in the incidence of heart failure subsequent to widespread statin usage may not be just due to the fact that statins may directly harm heart muscle cells, but also to the possibility that they indirectly put them in harm's way to the bacteria and viruses that have broken through the protective arterial wall.
The most clear and unambiguous benefit of statin drugs is that they reduce the incidence of nonfatal heart attacks in men in their 50's. The mechanism by which they achieve this outcome is surely directly tied to their ability to reduce the concentration of LDL in the blood. In careful studies of atherosclerosis, it has been determined that cholesterol in LDL plays a critical role in all stages of the atherosclerotic process. When the supply of LDL is reduced, the entire process is slowed down and the heart attack is delayed or possibly even arrested.
This is surely a good thing? Well, it seems to me that the atherosclerotic process is so intricate and so purposeful that it is hard to believe it plays no role in sustaining health. An excellent and widely referenced article written in 1995 on atherosclerosis [28] provides a fascinating account of all that happens in between the time that the LDL first penetrates the vessel wall and the time of the acute event triggering the heart attack.
Under normal circumstances, the cholesterol enters and leaves the artery wall at the same pace, and no fatty streak accumulates. However, sometimes the LDL "decides" to linger in the wall and also transforms to a weakly oxidized state. This oxidation is a signaling device that encourages white blood cells to join the party. They in turn release chemicals which further oxidize the LDL and trigger an inflammatory response. The newly arrived white blood cells are converted into macrophages, and the LDL, which had been hanging in the extracellular matrix, now take up semi-permanent residence inside the macrophages that are being steadily recruited from the blood supply. Once the LDL becomes highly oxidized it can even become toxic to the macrophages. They release their lipid (fat) droplets which are then consumed by nearby smooth muscle cells lining the artery wall. Over time, the resulting lesion grows outward until it eventually reaches the adventitia, the outermost layer of the artery wall. This situation is deemed a crisis condition, presumably because any further expansion in that direction would penetrate into the heart muscle.
Highly oxidized LDL penetrating all the way to the adventitia triggers a remarkable series of events intent on closing off the artery. High concentrations of "tissue factor" are released from the macrophages, and this tissue factor induces blood clotting by the platelets. The oxidized LDL also inhibits vasodilation, causing the vessel to constrict and furthering the goal of complete closure. Plaque rupture ensues, and more platelets are recruited to the wound site to further encourage a blood clot. In short, systematic biological mechanisms have been preprogrammed to shut down and isolate this segment of the heart.
What could possibly be a good reason to want to kill off a segment of the heart? The article that so beautifully laid out the sequence of events leading to a heart attack never mentioned the idea of an infective agent. However, the entire process would suddenly make sense if you imagine that, when LDL first entered the artery wall, it encountered an infective agent such as a bacterium or a virus, and it was this that triggered it to linger in the artery wall and enter the mildly oxidized state. The macrophages were then recruited to release toxic chemicals with the intent of disabling or even killing the viruses, and then to consume their debris. Meanwhile, the LDL could work on the parallel task of neutralizing toxins released by the infective agents. Further penetration towards the outer wall of the artery was necessitated because the viruses or bacteria were advancing in that direction. Once the enemy reached the outer wall, a crisis ensued because the next step would be penetration of the virus or bacterium into the heart muscle. Such an infection of the heart itself, myocarditis, was something to be avoided at all cost. A minor heart attack, which would essentially turn this segment of the heart into necrotic tissue, would also isolate the infective agent, a preferred outcome to the alternative of letting the infective agent grow unchecked within the heart muscle, leading directly to heart failure.
The notion of heart disease being due to an infective agent was proposed over two decades ago, and is gaining increased traction in recent times. One clear possibility is the extremely common herpes virus, also known as HCMV (Human Cytomegalovirus), which is estimated to infect from 60 to 99 percent of the world's population [3]. Several distinct observations are strongly suggestive of a role played by these viruses [22]. One such observation is that they are capable of triggering many of the steps involved in the above process of atherosclerosis. Another line of evidence comes from a clinical study that showed that patients with high titres of CMV antibodies were at greater risk to atherosclerosis. Direct evidence of their existence in atherosclerotic lesions has been found in the form of HCMV nucleic acids, detected in 90% of the severe atherosclerotic lesions that were examined. A final line of evidence comes from transplant patients --those who tested positive for HCMV infection were at much higher risk to arterial blockage.
A compelling argument for a relationship between an infective agent and atherosclerosis is in the case of children who were infected with typhoid fever. As early as 1911, Klotz and Manning [12] observed that atherosclerosis was particularly pronounced in children who had died from typhoid fever. They concluded that the production of fatty tissue in the arterial wall was the result of a direct irritation of that tissue by the presence of infection or toxins. Many studies have implicated a variety of other common infective agents as being cofactors in causing arterial disease. These include Chlamydia pneumoniae (a common source of pneumonia), Helicobacter pylori (the bacterium that causes stomach ulcers), and HSV and CMV (the one discussed above), both of which cause Herpes [16].
Another indirect argument for the relationship between infection and heart disease is that people who experience an acute heart attack or stroke have disproprortionately just recovered from an infectious disease. These diseases include tuberculosis, sepsis, HIV, chickenpox, tooth infections, and infections of the urinary tract. People with heart disease are encouraged to take steps to prevent gum disease, due to the observed correlation between infections in the gum and atherosclerosis.
A strong proponent of the theory that heart disease is the result of an infective agent is Uffe Ravnskov, a Swedish doctor who has been a tireless advocate of cholesterol as a much-abused and vital biological substance. In his recent book on cholesterol [21], the next-to-last chapter, titled simply "The Real Cause," argues persuasively for the point of view that atherosclerosis is the direct result of infective agents, and also makes a case for LDL's critical role in plaque build-up to protect against the infective agents. Oxidation is the usual way that macrophages destroy bacteria and viruses. Thus the presence of intense oxidation in the plaque is very suggestive of an attempt to neutralize a pathogen. LDL is able to bind and neutralize the alfa-toxin produced by staphylococcus baceteria, and, as we have seen before, it also neutralizes lipopolysccharide, another common bacterial endotoxin. By subsequently changing their structure to induce the macrophages to consume them, the LDL particles effectively render inert the bacteria and their harmful products.
The endotoxins that are released by bacteria are thus clearly implicated in heart disease. Since LDL can bind with and neutralize bacterial endotoxins, one reason why it might settle in the arterial wall, then, is to be available to neutralize the endotoxins of resident bacteria. It has also been shown that bacterial endotoxin stimulates the expression of tissue factor by macrophages (cells that were derived from the white blood cells) [24]. As we have seen from the above discussion on atherosclerosis, tissue factor is probably the single most contributory component for initiating the final cascade in a heart attack. This would presumably occur because the presence of unneutralized endotoxin indicates that the body's defenses have lost the battle against the bacteria at this site. Statins have been shown to inhibit the migration of white blood cells to inflammatory sites [27], which would reduce the bioavailability of tissue factor and therefore possibly prevent the heart attack, but would allow the bacteria and their endotoxin to remain in place and continue to do harm to the surrounding tissues, eventually invading the heart muscle itself.
Thus, the observed rapid rise in the incidence of heart failure subsequent to widespread statin usage may not be just due to the fact that statins may directly harm heart muscle cells, but also to the possibility that they indirectly put them in harm's way to the bacteria and viruses that have broken through the protective arterial wall.
Tuesday, July 21, 2009
Statins, Pregnancy, Sepsis, Cancer, Heart Failure: A Critical Analysis
Introduction
Over the last few decades, the American pharmaceutical industry (henceforth, "Big Pharma") has applied a very successful formula to market fear and convert it into a multi-billion dollar industry. The algorithm goes like this:
In a substitution of variables, the substance is cholesterol, the disease is heart disease, and the drug is Lipitor, and, voila! Through aggressive advertising campaigns, Big Pharma has managed to convince the American public and the American doctors that statin drugs are the best thing since sliced bread.
But are they right? I think the evidence shows that very few people currently taking statin drugs are actually benefiting from them. Furthermore, many of them are actually worse off than they would have been had they never been on statins. Below, I will argue that any benefits incurred in combating heart disease are more than offset by increased susceptibility to fetal damage, toxic infection, and cancer.
I am certainly not alone in my concern about the ever increasing usage of statin drugs to fight a "disease," "hypercholesterolemia" [high cholesterol], that I would argue is not a disease at all. The Weston A. Price Foundation is trying hard to spread the word about the many roles of cholesterol and the myriad side effects associated with statin usage. They share with me the growing alarm over the ever widening definition of who qualifies for statin drugs:
"Who suffers from hypercholesterolemia? Peruse the medical literature of 25 or 30 years ago and you'll get the following answer: any middle-aged man whose cholesterol is over 240 with other risk factors, such as smoking or overweight. After the Cholesterol Consensus Conference in 1984, the parameters changed; anyone (male or female) with cholesterol over 200 could receive the dreaded diagnosis and a prescription for pills. Recently that number has been moved down to 180. If you have had a heart attack, you get to take cholesterol-lowering medicines even if your cholesterol is already very low--after all, you have committed the sin of having a heart attack so your cholesterol must therefore be too high. The penance is a lifetime of cholesterol-lowering medications along with a boring lowfat diet. But why wait until you have a heart attack? Since we all labor under the stigma of original sin, we are all candidates for treatment. Current edicts stipulate cholesterol testing and treatment for young adults and even children." (Statin Drugs: the Problem) .
Let me first briefly introduce a bit of biology and terminology. Cholesterol is a biological substance that is a direct precursor to many very important substances, including the sex hormones estrogen and testosterone, the adrenal hormones hydrocortisone and aldosterone, bile acids which help you digest fats, and, most especially, vitamin D. It is well known that vitamin D plays a critical role in fighting infection and cancer, in addition to its essential role in calcium metabolism and bone health. Since cholesterol is so crucial to well-being, the body is able to manufacture as much as it needs in the liver, even in the absence of a supply from food sources. There is plenty of evidence that cholesterol is protective against infection, a topic that will be central to this essay. (Cholesterol Benefits) .
When you have your cholesterol measured, the numbers will come back factored into three components: LDL, HDL, and "other." In simple terminology, LDL delivers cholesterol (from the liver) to the peripheral tissues, and HDL delivers cholesterol (e.g., from food sources) to the liver, where it is converted to bile acids and released into the digestive system to break down consumed fats. LDL is the one that is usually labelled as "bad," but, as you will see later, this is a misnomer.
Big Pharma is intent on getting as many people as possible on as high a dose of statins as they can possibly justify. They are arguing now that people whose cholesterol levels are fine should take statins if their C-reactive protein, an indicator of inflammation, is high (C-Reactive Protein and Heart Disease) . They also claim that people with a known heart condition should aim to achieve an LDL level below 70 mg/dl ( 70 mg/dl LDL Goal ) . This can be accomplished (relatively easily in many cases) by taking 80 mg (four times the standard dosage) of a statin drug every day. They are now even prescribing statins for women in their 20's who are married and fertile, without regard to the damaging effect these drugs are known to have on a fetus.
What I find particularly frustrating, and what is perhaps my main reason for writing this essay, is that, in my view, many of the health benefits of high cholesterol are currently being mis-represented, paradoxically, as benefits of statin drugs. There is currently a barrage of news items on the Web claiming that statins are protective against cancer, sepsis, and Alzheimers' disease. The researchers behind the retrospective studies where an apparently beneficial effect is observed are careful to say that "randomized controlled studies have yet to be conducted," but the media miss those subtleties and turn the claims into "facts." At the same time, when it became clear that very low values of LDL are problematic for both infection and cancer, Big Pharma tried to distance itself from the tight association statin drugs have with cholesterol levels. Incredibly, they claim that, because low LDL is problematic regardless of whether it occurs naturally or artificially through statin use, statins are somehow exonerated. While I agree with their claim that statins are not "carcinogenic," in the sense that they don't directly cause cancer, statistics show that, over the long term, people who sustain a lower cholesterol level in the blood are at higher risk for cancer (and infection) than people with high cholesterol. Essentially, by taking a statin, you are shifting the odds on what you die of. Pay the money, suffer the side effects, and as a result you may end up dying of cancer or a runaway infection before you would have died of heart disease if you had never taken the drug in the first place.
In the next section, I hope to make it clear that one demographic that should never be prescribed a statin drug is pre-menopausal women. In the following sections I will discuss sepsis (blood poisoning), and cancer, and will show how Big Pharma has successfully manipulated the truth to make it appear that statins are protective against both of these, when in fact the exact opposite is true. The last section before the summary presents the infectious theory of atherosclerosis, which has recently received considerable attention. I will describe, in as simple terms as possible, how cholesterol may play a central role in the artery wall in fighting the infective agent. The arguments presented there lead to the conclusion that statins work against even the long-term health of the heart itself.
Over the last few decades, the American pharmaceutical industry (henceforth, "Big Pharma") has applied a very successful formula to market fear and convert it into a multi-billion dollar industry. The algorithm goes like this:
- find a substance whose concentration can be measured cheaply
- find a prevalent disease whose presence correlates with a high concentration of that substance
- find a drug that reduces the concentration of that substance
- advertise aggressively to the general public and medical professionals, claiming a miracle cure.
In a substitution of variables, the substance is cholesterol, the disease is heart disease, and the drug is Lipitor, and, voila! Through aggressive advertising campaigns, Big Pharma has managed to convince the American public and the American doctors that statin drugs are the best thing since sliced bread.
But are they right? I think the evidence shows that very few people currently taking statin drugs are actually benefiting from them. Furthermore, many of them are actually worse off than they would have been had they never been on statins. Below, I will argue that any benefits incurred in combating heart disease are more than offset by increased susceptibility to fetal damage, toxic infection, and cancer.
I am certainly not alone in my concern about the ever increasing usage of statin drugs to fight a "disease," "hypercholesterolemia" [high cholesterol], that I would argue is not a disease at all. The Weston A. Price Foundation is trying hard to spread the word about the many roles of cholesterol and the myriad side effects associated with statin usage. They share with me the growing alarm over the ever widening definition of who qualifies for statin drugs:
"Who suffers from hypercholesterolemia? Peruse the medical literature of 25 or 30 years ago and you'll get the following answer: any middle-aged man whose cholesterol is over 240 with other risk factors, such as smoking or overweight. After the Cholesterol Consensus Conference in 1984, the parameters changed; anyone (male or female) with cholesterol over 200 could receive the dreaded diagnosis and a prescription for pills. Recently that number has been moved down to 180. If you have had a heart attack, you get to take cholesterol-lowering medicines even if your cholesterol is already very low--after all, you have committed the sin of having a heart attack so your cholesterol must therefore be too high. The penance is a lifetime of cholesterol-lowering medications along with a boring lowfat diet. But why wait until you have a heart attack? Since we all labor under the stigma of original sin, we are all candidates for treatment. Current edicts stipulate cholesterol testing and treatment for young adults and even children." (Statin Drugs: the Problem) .
Let me first briefly introduce a bit of biology and terminology. Cholesterol is a biological substance that is a direct precursor to many very important substances, including the sex hormones estrogen and testosterone, the adrenal hormones hydrocortisone and aldosterone, bile acids which help you digest fats, and, most especially, vitamin D. It is well known that vitamin D plays a critical role in fighting infection and cancer, in addition to its essential role in calcium metabolism and bone health. Since cholesterol is so crucial to well-being, the body is able to manufacture as much as it needs in the liver, even in the absence of a supply from food sources. There is plenty of evidence that cholesterol is protective against infection, a topic that will be central to this essay. (Cholesterol Benefits) .
When you have your cholesterol measured, the numbers will come back factored into three components: LDL, HDL, and "other." In simple terminology, LDL delivers cholesterol (from the liver) to the peripheral tissues, and HDL delivers cholesterol (e.g., from food sources) to the liver, where it is converted to bile acids and released into the digestive system to break down consumed fats. LDL is the one that is usually labelled as "bad," but, as you will see later, this is a misnomer.
Big Pharma is intent on getting as many people as possible on as high a dose of statins as they can possibly justify. They are arguing now that people whose cholesterol levels are fine should take statins if their C-reactive protein, an indicator of inflammation, is high (C-Reactive Protein and Heart Disease) . They also claim that people with a known heart condition should aim to achieve an LDL level below 70 mg/dl ( 70 mg/dl LDL Goal ) . This can be accomplished (relatively easily in many cases) by taking 80 mg (four times the standard dosage) of a statin drug every day. They are now even prescribing statins for women in their 20's who are married and fertile, without regard to the damaging effect these drugs are known to have on a fetus.
What I find particularly frustrating, and what is perhaps my main reason for writing this essay, is that, in my view, many of the health benefits of high cholesterol are currently being mis-represented, paradoxically, as benefits of statin drugs. There is currently a barrage of news items on the Web claiming that statins are protective against cancer, sepsis, and Alzheimers' disease. The researchers behind the retrospective studies where an apparently beneficial effect is observed are careful to say that "randomized controlled studies have yet to be conducted," but the media miss those subtleties and turn the claims into "facts." At the same time, when it became clear that very low values of LDL are problematic for both infection and cancer, Big Pharma tried to distance itself from the tight association statin drugs have with cholesterol levels. Incredibly, they claim that, because low LDL is problematic regardless of whether it occurs naturally or artificially through statin use, statins are somehow exonerated. While I agree with their claim that statins are not "carcinogenic," in the sense that they don't directly cause cancer, statistics show that, over the long term, people who sustain a lower cholesterol level in the blood are at higher risk for cancer (and infection) than people with high cholesterol. Essentially, by taking a statin, you are shifting the odds on what you die of. Pay the money, suffer the side effects, and as a result you may end up dying of cancer or a runaway infection before you would have died of heart disease if you had never taken the drug in the first place.
In the next section, I hope to make it clear that one demographic that should never be prescribed a statin drug is pre-menopausal women. In the following sections I will discuss sepsis (blood poisoning), and cancer, and will show how Big Pharma has successfully manipulated the truth to make it appear that statins are protective against both of these, when in fact the exact opposite is true. The last section before the summary presents the infectious theory of atherosclerosis, which has recently received considerable attention. I will describe, in as simple terms as possible, how cholesterol may play a central role in the artery wall in fighting the infective agent. The arguments presented there lead to the conclusion that statins work against even the long-term health of the heart itself.
2. Statins and Pregnancy
You may not be old enough to remember the disaster incurred by the widespread practice in Europe in the 1950's of treating depression with the then newly discovered drug Thalidomide. When you take a Lipitor tablet you are taking a drug that, like Thalidomide, is labeled "Class X" with respect to its potential harm to the fetus, and is even worse than Thalidomide in terms of the kind of damage it can do to your unborn child. A woman who is in the childbearing age group should never be advised to take a statin drug. While there are warnings associated with the ads and on the labels claiming that you should "stop taking Lipitor" should you become pregnant, the drug companies seem intent on hushing up the fact that these drugs are toxic to the developing fetus.
Clearly it would be unethical to conduct a controlled experiment that intentionally exposes a pregnant woman to statins, and therefore such controlled studies have not been done. However, in one of the few available retrospective studies of statins and pregnancy, researchers from the U.S. National Institutes of Health found that statin use during the first trimester of pregnancy led to severe central nervous system defects as well as limb deformities. Twenty out of 52 women who had been exposed to statins during the first trimester had babies with severe deformities, which is nearly a 40% rate of severe birth
"Of the 20 babies born with malformations, five had severe central nervous system defects, and five had malformed limbs. One baby had both, according to Muenke. There were also two cases of a very rare birth defect called holoprosencephaly, which occurs when the brain fails to divide properly." (Statins and Birth Defects) .
Doctors in Liverpool have even had the audacity to propose that statins be prescribed to pregnant women, an idea that these authors find wildly disturbing: (Statins during Pregnancy) . There seems to be a general lack of awareness, even among doctors, of the degree of harm these drugs can inflict on the developing fetus.
Great Britain now has the dubious distinction of being the only country where you can buy statin drugs over the counter (NonPrescription Statins) . This means that any naive young woman thinking she can self-treat high cholesterol may end up with a severely malformed baby, and chances are she won't even realize it's due to the drug.
Clearly it would be unethical to conduct a controlled experiment that intentionally exposes a pregnant woman to statins, and therefore such controlled studies have not been done. However, in one of the few available retrospective studies of statins and pregnancy, researchers from the U.S. National Institutes of Health found that statin use during the first trimester of pregnancy led to severe central nervous system defects as well as limb deformities. Twenty out of 52 women who had been exposed to statins during the first trimester had babies with severe deformities, which is nearly a 40% rate of severe birth
"Of the 20 babies born with malformations, five had severe central nervous system defects, and five had malformed limbs. One baby had both, according to Muenke. There were also two cases of a very rare birth defect called holoprosencephaly, which occurs when the brain fails to divide properly." (Statins and Birth Defects) .
Doctors in Liverpool have even had the audacity to propose that statins be prescribed to pregnant women, an idea that these authors find wildly disturbing: (Statins during Pregnancy) . There seems to be a general lack of awareness, even among doctors, of the degree of harm these drugs can inflict on the developing fetus.
Great Britain now has the dubious distinction of being the only country where you can buy statin drugs over the counter (NonPrescription Statins) . This means that any naive young woman thinking she can self-treat high cholesterol may end up with a severely malformed baby, and chances are she won't even realize it's due to the drug.
3. Very Low LDL: Good or Bad?
In the following pages, I will first make a case for why very low values of LDL are dangerous. I will then tell two remarkable stories about how statin makers are trying to convince the media and the public that black is white: they argue that statins are actually protective against both cancer and sepsis (blood poisoning), whereas the evidence is the exact opposite, as I will now show.
I am going to start my story with a recent article that appeared in the Annals of Clinical and Laboratory Science in 2007 (Low LDL Bad) . This article involved a very simple study, inspired by the recent practice of cardiologists to recommend to their patients with known heart disease that they more aggressively lower their LDL cholesterol levels. The consequences of a very low LDL level, as evidenced by the outcome of the experiment described in the above article, can be dramatic and alarming. The authors examined 203 patients' charts in a hospital and divided them into two groups: those whose LDL was below 70 mg/dl, and those whose LDL was above 70 mg/dl. They found that the below 70 group had a fifteen fold increase in the incidence of cancer, and a five fold increase in the incidence of sepsis (more familiarly known as blood poisoning or septicemia), when compared with the above-70 group. Thus, nearly all of the patients who had cancer and most of the patients who had sepsis also had low LDL, strongly implying that people with low values of LDL are much more likely to suffer from cancer and dangerous infection than the general population.
Statin proponents are scrambling to come up with convoluted explanations that exonerate statin drugs, as evidenced in the way another article along similar lines is pitched [10] (Not Even Looking for Cancer) . Even though they weren't initially investigating cancer at all, but were rather concerned about liver and muscle damage, these authors found a highly significant (p=.009) inverse correlation between achieved LDL levels and cancer -- the lower the LDL level the higher the incidence of cancer. The review process for this article was very heated, and an argument was made that it should not be published because it might discourage people from taking their statin drugs. It starts to become humorous when you read the explanation developed here: (Statins aren't to Blame) . The argument goes like this: people who have natural low values of LDL (< 70 mg/dl) have increased cancer risk even if they aren't taking statin drugs. Statin drugs don't directly cause cancer, they just promote it indirectly by knocking down your LDL levels into the range where increased risk occurs. Guns don't kill you, they just release bullets that do.
I am going to start my story with a recent article that appeared in the Annals of Clinical and Laboratory Science in 2007 (Low LDL Bad) . This article involved a very simple study, inspired by the recent practice of cardiologists to recommend to their patients with known heart disease that they more aggressively lower their LDL cholesterol levels. The consequences of a very low LDL level, as evidenced by the outcome of the experiment described in the above article, can be dramatic and alarming. The authors examined 203 patients' charts in a hospital and divided them into two groups: those whose LDL was below 70 mg/dl, and those whose LDL was above 70 mg/dl. They found that the below 70 group had a fifteen fold increase in the incidence of cancer, and a five fold increase in the incidence of sepsis (more familiarly known as blood poisoning or septicemia), when compared with the above-70 group. Thus, nearly all of the patients who had cancer and most of the patients who had sepsis also had low LDL, strongly implying that people with low values of LDL are much more likely to suffer from cancer and dangerous infection than the general population.
Statin proponents are scrambling to come up with convoluted explanations that exonerate statin drugs, as evidenced in the way another article along similar lines is pitched [10] (Not Even Looking for Cancer) . Even though they weren't initially investigating cancer at all, but were rather concerned about liver and muscle damage, these authors found a highly significant (p=.009) inverse correlation between achieved LDL levels and cancer -- the lower the LDL level the higher the incidence of cancer. The review process for this article was very heated, and an argument was made that it should not be published because it might discourage people from taking their statin drugs. It starts to become humorous when you read the explanation developed here: (Statins aren't to Blame) . The argument goes like this: people who have natural low values of LDL (< 70 mg/dl) have increased cancer risk even if they aren't taking statin drugs. Statin drugs don't directly cause cancer, they just promote it indirectly by knocking down your LDL levels into the range where increased risk occurs. Guns don't kill you, they just release bullets that do.
4. Do Statins Protect against Sepsis?
Quite surprisingly, you can easily find web pages that hail the benefits of statins beyond their ability to lower cholesterol (already a dubious achievement). The claims they make directly contradict the actual effects of statins. For example, if you do a web search on "statins cancer", you will find several hits claiming that statins may be protective against cancer. Several recent articles on the Web have suggested that statins may protect against sepsis. I am almost certain that both of these claims are false.
We'll start with sepsis, and with an article that illustrates how sloppy science gets turned into truth when it migrates into the media. (Statins Reduce Sepsis Risk) . I quote here the lead sentence of the story:
"Cholesterol-lowering drugs can reduce the risk of severe infection in patients suffering from heart disease or stroke, scientists said on Wednesday."
This sounds like a fact, but instead it is the result of a flawed study, as I will argue below. The conclusion was drawn on the basis of a retrospective study of patients who had had a heart attack or stroke. "Retrospective" means to take a look back at something that has already taken place. Some of the patients had been prescribed statins and some had not, a decision surely based on their cholesterol profile. Thus, those who were not prescribed statins must have had naturally occurring low cholesterol, even though they suffered from a disease commonly treated with statins. Although high cholesterol is correlated with heart disease incidence, it is by no means the case that if you have heart disease you must have high cholesterol.
Another very strong risk factor for heart disease and stroke is diabetes, (in fact, it is sometimes referred to as a cardiovascular disease) (Diabetes and Heart Disease) . (Diabetes and Stroke) . Diabetes is also a risk factor for sepsis (Diabetes and Sepsis) , because untreated diabetes often leads to sores in the extremities that won't heal, which can lead to subsequent gangrene and amputations. It is quite plausible that those in the retrospective study who did not have high cholesterol were more likely to have diabetes (the causative agent of their heart attack or stroke), a condition which causes increased risk to sepsis.
The above claim that cholesterol-lowering drugs can reduce the risk of severe infection in patients suffering from heart disease or stroke is directly contradicted in the conclusion of an excellent article that carefully examined several studies on sepsis. These authors concluded that statin therapy should be temporarily halted during a sepsis event [27]. (Statins Following Sepsis Event) .
"Statins are effective at lowering lipid levels, but lipids are the wrong target in sepsis. Higher lipid levels are desirable in these patients."
He goes on to say: "Research has shown that hypocholesterolemia [low cholesterol] in critical illness and multisystem organ failure correlates with decreased patient survival rates." This can be translated into "if your cholesterol is low, you have a worse chance of surviving."
A careful study of all the available evidence that statins may protect against sepsis, titled simply, "Statins and Sepsis," [7] was published by Professor Fang Gao at the University of Warwick in the U.K. in the British Journal of Anesthesia in 2008. (Statins and Sepsis: Review Study) . At the end of the study, he wrote this caveat: "However, there have been no RCT [randomized controlled clinical trials] of statins in sepsis, and large randomized controlled clinical trials with clinically relevant primary endpoints are desperately needed." In the paper, he mentioned the ASEPSIS trial, that was underway at the time, and which he claimed would be completed by 2008. A "Declaration of interest" at the bottom of the paper said the following:
"Professor Gao is the Chief Investigator of RCT on Statin therapy in the ASEPSIS trial. The trial received a pump-prime research grant from Pfizer. Professor Gao and Dr Thickett have received travelling sponsorships from pharmaceutical and industrial companies to attend national and international conferences."
I.e., Professor Gao receives funding and perks from Big Pharma that surely influence his research bias.
Since it is now June, 2009, I was eager to find the results of the ASEPSIS trial on the Web. I did find a pointer to the trial itself, (ASEPSIS Trial) , and a very encouraging title: "Randomised double-blind placebo-controlled trial of 40 mg/day of Atorvastatin on reduction in severity of SEPSIS in ward patients." The trial web site indicated that indeed the trial had been completed in January, 2008, i.e., eighteen months ago. But there was nothing there to indicate what the outcome was. The web search turned up no other pointer to this trial -- no papers, no media coverage. You can be sure that if this trial had had an outcome favorable to statins, it would have been all over the media. Thus, it is highly likely that this randomized double-blind placebo-controlled trial showed the exact opposite of the effect that was so eagerly anticipated. Once you remove the cholesterol bias, the effect goes away.
We'll start with sepsis, and with an article that illustrates how sloppy science gets turned into truth when it migrates into the media. (Statins Reduce Sepsis Risk) . I quote here the lead sentence of the story:
"Cholesterol-lowering drugs can reduce the risk of severe infection in patients suffering from heart disease or stroke, scientists said on Wednesday."
This sounds like a fact, but instead it is the result of a flawed study, as I will argue below. The conclusion was drawn on the basis of a retrospective study of patients who had had a heart attack or stroke. "Retrospective" means to take a look back at something that has already taken place. Some of the patients had been prescribed statins and some had not, a decision surely based on their cholesterol profile. Thus, those who were not prescribed statins must have had naturally occurring low cholesterol, even though they suffered from a disease commonly treated with statins. Although high cholesterol is correlated with heart disease incidence, it is by no means the case that if you have heart disease you must have high cholesterol.
Another very strong risk factor for heart disease and stroke is diabetes, (in fact, it is sometimes referred to as a cardiovascular disease) (Diabetes and Heart Disease) . (Diabetes and Stroke) . Diabetes is also a risk factor for sepsis (Diabetes and Sepsis) , because untreated diabetes often leads to sores in the extremities that won't heal, which can lead to subsequent gangrene and amputations. It is quite plausible that those in the retrospective study who did not have high cholesterol were more likely to have diabetes (the causative agent of their heart attack or stroke), a condition which causes increased risk to sepsis.
The above claim that cholesterol-lowering drugs can reduce the risk of severe infection in patients suffering from heart disease or stroke is directly contradicted in the conclusion of an excellent article that carefully examined several studies on sepsis. These authors concluded that statin therapy should be temporarily halted during a sepsis event [27]. (Statins Following Sepsis Event) .
"Statins are effective at lowering lipid levels, but lipids are the wrong target in sepsis. Higher lipid levels are desirable in these patients."
He goes on to say: "Research has shown that hypocholesterolemia [low cholesterol] in critical illness and multisystem organ failure correlates with decreased patient survival rates." This can be translated into "if your cholesterol is low, you have a worse chance of surviving."
A careful study of all the available evidence that statins may protect against sepsis, titled simply, "Statins and Sepsis," [7] was published by Professor Fang Gao at the University of Warwick in the U.K. in the British Journal of Anesthesia in 2008. (Statins and Sepsis: Review Study) . At the end of the study, he wrote this caveat: "However, there have been no RCT [randomized controlled clinical trials] of statins in sepsis, and large randomized controlled clinical trials with clinically relevant primary endpoints are desperately needed." In the paper, he mentioned the ASEPSIS trial, that was underway at the time, and which he claimed would be completed by 2008. A "Declaration of interest" at the bottom of the paper said the following:
"Professor Gao is the Chief Investigator of RCT on Statin therapy in the ASEPSIS trial. The trial received a pump-prime research grant from Pfizer. Professor Gao and Dr Thickett have received travelling sponsorships from pharmaceutical and industrial companies to attend national and international conferences."
I.e., Professor Gao receives funding and perks from Big Pharma that surely influence his research bias.
Since it is now June, 2009, I was eager to find the results of the ASEPSIS trial on the Web. I did find a pointer to the trial itself, (ASEPSIS Trial) , and a very encouraging title: "Randomised double-blind placebo-controlled trial of 40 mg/day of Atorvastatin on reduction in severity of SEPSIS in ward patients." The trial web site indicated that indeed the trial had been completed in January, 2008, i.e., eighteen months ago. But there was nothing there to indicate what the outcome was. The web search turned up no other pointer to this trial -- no papers, no media coverage. You can be sure that if this trial had had an outcome favorable to statins, it would have been all over the media. Thus, it is highly likely that this randomized double-blind placebo-controlled trial showed the exact opposite of the effect that was so eagerly anticipated. Once you remove the cholesterol bias, the effect goes away.
5. Do Statins Cause Sepsis?
Researchers who are trying to make sense of the idea that statins might protect against sepsis are led to the false conclusion that statins must have some other biological effect ( besides their dramatic ability to interfere with cholesterol production) that is making them protective against sepsis. This other effect would protect against infection and inflammation. Yet protecting against infection and inflammation is something that cholesterol itself does extremely well. Based on biology, I would expect that, if the difference in cholesterol levels between the control group and the treatment group are eliminated, the apparent beneficial effect of statins for sepsis would disappear. In fact, I would expect the effect to go in the wrong direction, i.e., statins cause an increased risk to sepsis.
An article by Wilson et al. [25] in the journal Critical Care studied changes in blood cholesterol levels following trauma, infection and multiple organ failure. I quote their abstract in full here:
"Hypocholesterolemia is an important observation following trauma. In a study of critically ill trauma patients, mean cholesterol levels were significantly lower (119 ± 44 mg/dl) than expected values (201 ± 17 mg/dl). In patients who died, final cholesterol levels fell by 33% versus a 28% increase in survivors. Cholesterol levels were also adversely affected by infection or organ system dysfunction. Other studies have illustrated the clinical significance of hypocholesterolemia. Because lipoproteins can bind and neutralize lipopolysaccharide, hypocholesterolemia can negatively impact outcome. New therapies directed at increasing low cholesterol levels may become important options for the treatment of sepsis." [25]
"Hypocholesterolemia" is low cholesterol. Patients who died had low cholesterol to begin with, and saw their cholesterol drop on average by 33%. Patients who survived experienced a 28% increase in cholesterol level over the course of the disease -- they were able to marshall all their defenses toward manufacturing cholesterol at full capacity to fight the disease. "Lipopolysaccharide" is another term for the endotoxins that bacteria release triggering a sepsis event. "Lipoproteins" is the second "L" in "LDL". So the statement, "lipoproteins can bind and neutralize lipopolysaccharide" means that cholesterol is mobilized to bind and neutralize the endotoxins released by bacteria during an acute phase of infection, the one thing that most critically needs to be done to get out of a sepsis crisis. The article advocates drugs to support increasing cholesterol levels, i.e., the exact opposite of a statin drug.
CAH (cholesterol-7alpha-hydroxylase) is an enzyme that plays an important role in the liver to break cholesterol down and dispose of it as bile acids. In experiments conducted on hamsters, Feingold et al.[6] (Endotoxins and CAH) exposed the hamsters to bacterial endotoxins and observed an immediate biological response that inhibited the activity of CAH, which then promoted the availability of more cholesterol to devote to fighting the infection. In the summary, they conclude, "Thus the decrease in CAH may play a role in facilitating the formation and secretion of lipoprotein in the liver, thereby contributing to host defense." I.e., by preventing the breakdown of cholesterol in the liver, more cholesterol is made available to fight the disease.
If statins lowered the risk of sepsis in the individual, then they should have done so in the general population as well, yet the results of epidemiological studies yield dramatically different results.
"In the United States, there were an estimated 750,000 cases of severe sepsis in 1995, resulting in 215,000 deaths, and there was an annualized increase in the incidence of sepsis of 8.7% between 1979 and 2000. Sepsis now rivals acute myocardial infarction as a frequent cause of death. It is the leading cause of death in noncoronary intensive care units (ICUs)." [27] (Sepsis is on the Rise) .
Let me repeat: 8.7% increase in sepsis incidence every year. Statin drugs were first introduced as prescription drugs in the 1980's, and have enjoyed steadily increasing usage statistics since then. (Statin History) . If they protect against sepsis, why does the incidence of sepsis keep going up every year as more and more people take statins?
The answer to this question is the same as the answer to the question of why the effect goes away when you perform a randomized double-blind trial. It is cholesterol, not statins, that protects against sepsis. In the retrospective studies, the control group are the ones who did not meet the requirements for statin prescription, i.e., who must have had very low cholesterol indeed, if they were not being prescribed statins in spite of heart disease or stroke. It is their low LDL that makes them susceptible to sepsis. In the placebo-controlled ASEPSIS trial, there would not have been a distinction in the pre-treatment cholesterol levels between the treatment group and the controls, and this is what caused the apparent benefit of statins to disappear: it was actually a benefit of cholesterol that was measured instead.
While it is less well known than the number one and number two killers, heart disease and cancer, sepsis is nonetheless a very nasty condition that kills fast and viciously. To quote from Wikipedia,
"In the United States, sepsis is the second-leading cause of death in non-coronary ICU patients, and the tenth-most-common cause of death overall according to data from the Centers for Disease Control and Prevention (the first being multiple organ dysfunction syndrome). Sepsis is common and also more dangerous in elderly, immunocompromised, and critically-ill patients. It occurs in 1-2% of all hospitalizations and accounts for as much as 25% of intensive-care unit (ICU) bed utilization. It is a major cause of death in intensive-care units worldwide, with mortality rates that range from 20% for sepsis to 40% for severe sepsis to >60% for septic shock." (Wikipedia on Sepsis) .
The flawed studies suggesting a link between taking statins and preventing sepsis are actually instead showing a link between very low cholesterol and increased sepsis susceptibility. Cholesterol is doing the work, and statins are stealing the credit. All the while, statins are slowly crippling the work horse.
As a final blow to the theory that statins may protect against infection, a carefully designed study that just came out has shown that statin drugs increase the risk of pneumonia requiring hospitalization in the elderly by 61% (Statins Increase Risk for Pneumonia) . The study, published in the British Medical Journal, involved over 3,000 Group Health patients. The study was inspired by the recent hype that statins might protect against infection, an idea that is looking more and more like the result of the benefits of high cholesterol rather than any immune resistance role for statins. The result is consistent with the view that the effect of statins to reduce cholesterol levels in the blood is actually serving to decrease immunity and promote infection.
An article by Wilson et al. [25] in the journal Critical Care studied changes in blood cholesterol levels following trauma, infection and multiple organ failure. I quote their abstract in full here:
"Hypocholesterolemia is an important observation following trauma. In a study of critically ill trauma patients, mean cholesterol levels were significantly lower (119 ± 44 mg/dl) than expected values (201 ± 17 mg/dl). In patients who died, final cholesterol levels fell by 33% versus a 28% increase in survivors. Cholesterol levels were also adversely affected by infection or organ system dysfunction. Other studies have illustrated the clinical significance of hypocholesterolemia. Because lipoproteins can bind and neutralize lipopolysaccharide, hypocholesterolemia can negatively impact outcome. New therapies directed at increasing low cholesterol levels may become important options for the treatment of sepsis." [25]
"Hypocholesterolemia" is low cholesterol. Patients who died had low cholesterol to begin with, and saw their cholesterol drop on average by 33%. Patients who survived experienced a 28% increase in cholesterol level over the course of the disease -- they were able to marshall all their defenses toward manufacturing cholesterol at full capacity to fight the disease. "Lipopolysaccharide" is another term for the endotoxins that bacteria release triggering a sepsis event. "Lipoproteins" is the second "L" in "LDL". So the statement, "lipoproteins can bind and neutralize lipopolysaccharide" means that cholesterol is mobilized to bind and neutralize the endotoxins released by bacteria during an acute phase of infection, the one thing that most critically needs to be done to get out of a sepsis crisis. The article advocates drugs to support increasing cholesterol levels, i.e., the exact opposite of a statin drug.
CAH (cholesterol-7alpha-hydroxylase) is an enzyme that plays an important role in the liver to break cholesterol down and dispose of it as bile acids. In experiments conducted on hamsters, Feingold et al.[6] (Endotoxins and CAH) exposed the hamsters to bacterial endotoxins and observed an immediate biological response that inhibited the activity of CAH, which then promoted the availability of more cholesterol to devote to fighting the infection. In the summary, they conclude, "Thus the decrease in CAH may play a role in facilitating the formation and secretion of lipoprotein in the liver, thereby contributing to host defense." I.e., by preventing the breakdown of cholesterol in the liver, more cholesterol is made available to fight the disease.
If statins lowered the risk of sepsis in the individual, then they should have done so in the general population as well, yet the results of epidemiological studies yield dramatically different results.
"In the United States, there were an estimated 750,000 cases of severe sepsis in 1995, resulting in 215,000 deaths, and there was an annualized increase in the incidence of sepsis of 8.7% between 1979 and 2000. Sepsis now rivals acute myocardial infarction as a frequent cause of death. It is the leading cause of death in noncoronary intensive care units (ICUs)." [27] (Sepsis is on the Rise) .
Let me repeat: 8.7% increase in sepsis incidence every year. Statin drugs were first introduced as prescription drugs in the 1980's, and have enjoyed steadily increasing usage statistics since then. (Statin History) . If they protect against sepsis, why does the incidence of sepsis keep going up every year as more and more people take statins?
The answer to this question is the same as the answer to the question of why the effect goes away when you perform a randomized double-blind trial. It is cholesterol, not statins, that protects against sepsis. In the retrospective studies, the control group are the ones who did not meet the requirements for statin prescription, i.e., who must have had very low cholesterol indeed, if they were not being prescribed statins in spite of heart disease or stroke. It is their low LDL that makes them susceptible to sepsis. In the placebo-controlled ASEPSIS trial, there would not have been a distinction in the pre-treatment cholesterol levels between the treatment group and the controls, and this is what caused the apparent benefit of statins to disappear: it was actually a benefit of cholesterol that was measured instead.
While it is less well known than the number one and number two killers, heart disease and cancer, sepsis is nonetheless a very nasty condition that kills fast and viciously. To quote from Wikipedia,
"In the United States, sepsis is the second-leading cause of death in non-coronary ICU patients, and the tenth-most-common cause of death overall according to data from the Centers for Disease Control and Prevention (the first being multiple organ dysfunction syndrome). Sepsis is common and also more dangerous in elderly, immunocompromised, and critically-ill patients. It occurs in 1-2% of all hospitalizations and accounts for as much as 25% of intensive-care unit (ICU) bed utilization. It is a major cause of death in intensive-care units worldwide, with mortality rates that range from 20% for sepsis to 40% for severe sepsis to >60% for septic shock." (Wikipedia on Sepsis) .
The flawed studies suggesting a link between taking statins and preventing sepsis are actually instead showing a link between very low cholesterol and increased sepsis susceptibility. Cholesterol is doing the work, and statins are stealing the credit. All the while, statins are slowly crippling the work horse.
As a final blow to the theory that statins may protect against infection, a carefully designed study that just came out has shown that statin drugs increase the risk of pneumonia requiring hospitalization in the elderly by 61% (Statins Increase Risk for Pneumonia) . The study, published in the British Medical Journal, involved over 3,000 Group Health patients. The study was inspired by the recent hype that statins might protect against infection, an idea that is looking more and more like the result of the benefits of high cholesterol rather than any immune resistance role for statins. The result is consistent with the view that the effect of statins to reduce cholesterol levels in the blood is actually serving to decrease immunity and promote infection.
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