Too Much of a Good Thing: High Dose Vitamin B Supplements, Heart Disease, Stroke and Cancer

For years it was widely believed that water soluble vitamins, including B-Complex, were relatively safe to consume in large quantities.  Many health claims have been made for B vitamins, including the prevention of heart disease, cancer, and dementia, but there is mounting evidence that high dose vitamin B supplementation does indeed carry risks, at least in certain populations.  Too much of a good thing?

High levels of homocysteine have been associated with an increased the risk for diabetic nephropathy, retinopathy, and vascular disease, and vitamin B supplementation has been shown to reduce homocysteine levels.  Therefore, it seemed reasonable to conduct a clinical trial of vitamin B in diabetics.   House and associates prospectively whether vitamin B might reduce the progression of a type of kidney disease common to diabetics.  The results of their study appeared in the April 28, 2010 edition of the Journal of the American Medical Association. They recruited 238 Type 1 and Type 2 diabetic patients with kidney disease (diabetic nephropathy), a precursor to chronic kidney disease. The patients were assigned to take a single combined B vitamin tablet (folic acid 2.5 mg, vitamin B6 25 mg, and vitamin B12 1 mg) or placebo, once daily. The mean follow-up period was 31.9 months.  Patients with diabetic nephropathy who received high-dose vitamin B therapy were at increased risk for kidney function decline, myocardial infarction and stroke.  (House AA. JAMA. 2010;303:1603-1609.)

The results of this study are consistent with the Norwegian Vitamin Trial (NORVIT). In this study, the combination of vitamin B6 and folic acid, as well as folic acid alone, effectively lowered homocysteine levels by 28% but did not have the expected beneficial effect on cardiovascular risk. At follow-up, the risk of stroke and MI was 18% in the placebo group, but in the combination B6 and folic acid group 23% of patients had a fatal or nonfatal stroke or MI, a statistically significant increase.   Of perhaps greater concern is an association found between vitamin B supplementation and cancer.  Ebbing and associates conducted further analysis of the NORVIT data, combining this with the Western Norway B Vitamin Intervention Trial data.  They reported treatment with folic acid plus vitamin B(12) was associated with increased cancer outcomes and all-cause mortality in patients with ischemic heart disease.  (Ebbing M et al.  Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA. 2009; 302(19):2152-3.)

This is another example of the limitations of the reductionist approach to illness and health.  The reductionist, as opposed to a holist approach, treats individuals complex “machines” that can be repaired by indentifying and mending malfunctioning component parts. This model works well for some medical problems—pinning and casting a broken bone as an example.  Problems such as type 2 diabetes, coronary heart disease, or depression are much more complex than a fracture, and there are no “single” broken parts or parts to fix.   In fact, treatments aimed to “fix” the broken part of the machine sometimes makes matters worse, often affecting some other “part” of the “machine”. Pharmaceutical advertisements would have us believe that depression can be fixed by balancing of neurotransmitters; that coronary artery disease can be fixed by drugs that lower lipids; that diabetes can be fixed with medications that lower blood glucose. But, on further examination, the limitations of this approach are evident. Serotonin reuptake inhibitors (e.g. Lexapro ®) do improve the mood of many depressed patients, but significant proportion suffers an adverse affect (e.g. sexual function). Statins (e.g. Zocor ®) lower cholesterol but are a frequent cause of muscle pain.  Thiazolidinedione medications (e.g. Avandia ®) lower blood glucose in diabetics but are known to cause fluid retention and congestive heart failure.

A few years ago, high levels of homocysteine are associated with renal and cardiovascular illness. Sinc vitamin B lowers homocysteine levels, it should, in theory, improve outcomes. This presumes that there is one cause, high homocysteine levels that can be treated with a simple “fix.” As is so often the case, altering one component of a complex system has untoward and unanticipated effects elsewhere. Humans are not machines, but complex organisms in dynamic interaction with internal (i.e. organ systems) and external environments.  We are part of an ecosystem, though we rarely think of ourselves in this way.  Our intestines and skin are inhabited by millions of bacteria without which we cannot live.  The human genome is itself constructed upon a backbone of DNA building blocks borrowed from species the predated our own. We evolved over millions of years, developing organ systems that work in harmony with each other, as well with the microbes that inhabit our bodies and with the larger ecosystem upon which we depend for food, oxygen, water, social interaction, etc.  From a holistic standpoint, illness occurs when there is a breakdown in the ecology—when things are out of balance.  In the case of vitamins, a diet deficient in essential vitamins leads to an imbalance that is corrected by a proper diet or, when vitamin rich food is unavailable, vitamin supplementation.  The concept that taking more vitamins than our ecosystem requires may be analogous to treating vegetable crops with more fertilizer than needed; there may be short term returns, but over-fertilizing places the plant at risk for disease as well as having negative consequences for the larger ecosystem.  While consuming more vitamin B than the diet would ordinarily provide does have the desired biological effect of reducing homocysteine levels, it also affects our ecosystem in ways we do not completely understand, possibly contributing to cardiovascular events, renal damage in diabetics, and cancer.

Beware all of the advertisements for dietary supplements that state “preliminary evidence” supports the importance of such and such in preventing or treating such and such.   We just don’t know long term consequences of messing with Mother Nature….

Viral Cause of Chronic Fatigue Syndrome?

Chronic Fatigue Syndrome (CFS) has long baffled physicians.  The condition is characterized by the new onset of severe fatigue of at least 6 months duration without another medical explanation. While sometimes regarded as a psychological problem, most physicians have suspected a viral or toxic cause because so many apparently healthy, young individuals have been reported to develop the condition.  In October 2009, it was reported that 68 of 101 patients with chronic fatigue syndrome (CFS) in the US were infected with the xenotropic murine leukaemia virus-related virus (XMRV), a virus previously linked to prostate cancer in some studies, but not in others. At last, the elusive cause of CFS had been identified, and a company is now selling a test to detect the causative virus!

The putative connection between CFS and XMRV was widely reported in the lay press. I first learned of these research findings in my morning reading of the Philadelphia Enquirer.  But is this virus really responsible for CFS?  New research casts serious doubts on the original report. Erlwein and associates screened their population of 186 CFS patients for the XMRV virus.*  They found no evidence of the virus in any of their patients.  I don’t recall reading a report about these new findings in the paper…  Good science rarely makes good press...  especially when reporting negative findings!


*Note: Commentors (below) raised concerns regarding the validity of this study.

Erlwein et al. Failure to detect the novel retrovirus XMRV in chronic fatigue syndrome. PloS one. 2010 Jan 6;5(1):e8519.

Guilty of "Treating the Numbers"

Warfarin (Coumadin ®) is a blood thinner use to treat deep vein thrombosis, pulmonary blood clots, and to prevent stroke.  This medication interferes with Vitamin K-dependent synthesis of various clotting factors but correct dosing can be challenging. Clinicians routinely monitor clotting by use of the INR (Prothrombin Time-International Normalized Ratio) test.  Warfarin has a narrow therapeutic index—just a little too much will result in a high INR with concomitant easy bruising, bleeding, and, sometimes, frank hemorrhage. Just a little too little and the INR remains normal placing patients at risk for thromboembolic events (e.g. stroke). When patients arrive in emergency departments because of bleeding complications related to warfarin, the standard treatment at one time was an injection of vitamin K.  This would normalize the PT-INR, but it often took days of warfarin treatment to reestablish a therapeutic INR. About 10 or so years ago I was a residency director and member of a hospital pharmacy committee.  I actively promoted the adoption of low dose oral vitamin K treatment as an alternative to injecting Vitamin K to “fix” the problem of a high INR.  This approach had the advantage of gradually bringing the INR into the normal range without “overshooting”.  I slept better knowing that I was treating the high INR. But was oral Vitamin K an effective in reducing bleeding risk for my patients, or was I just “fixing the number”?   In a study published in the Annals of Internal Medicine (Ann Intern Med 2009; 150(5):293-300 ), Crowther and associates chose to study patients with a high INR who were not actively bleeding.   About half the patients received Vitamin K and half placebo.  As expected those patients receiving Vitamin K normalized the INR faster (happy doctors and nurses!).  However, there were no differences in bleeding events.   “Fixing the numbers” did not fix the real problem—bleeding risk.  

This study highlights a common problem in medicine—“treating the numbers.”  One would assume that medications equally effective in “treating the numbers” would be equally effective in reducing morbidity or morality.  We know that high blood pressure, cholesterol, and glucose (blood sugar) cause heart attacks and strokes, so we prescribe medications to normalize blood pressure, cholesterol and glucose.  Unfortunately, the human body is very complex and some medications are very effective at “fixing the numbers,” but not so effective in preventing disease complications.  Clinicians are well aware of this problem.  

In the 1980’s, pharmaceutical companies heavily marketed a class of antihypertensive (blood pressure) medications known as calcium channel blockers as at least as effective as older medication in reducing blood pressure with fewer side effects.  Doctors switched patients to these new, albeit more expensive, medications in droves.  As it turned out, calcium channel blocers were not superior in preventing the complications of hypertension and these medications are now consider second line for most patients.   TV watcher will recall the commercials for Vytorin ®, a combination drug (ezetimibe and simvastatin) intended to treat the “two causes” of high cholesterol—diet and heredity (recall those cute aunts and uncles?). Yes, Vytorin ® did a great job of “fixing the numbers” but was not effective in other regards.  The ENHANCE trial of Vytorin ® was designed to show that ezetimibe could reduce the growth of fatty plaques in arteries. Instead, it reported that adding ezetimibe resulted in plaque growth. The ARBITER 6–HALTS study found that ezetimibe treated patients had more major cardiovascular events than those treated with niacin.  Many medications equally reduce blood sugar, but are not equal in preventing the complications of diabetes. 

 All doctors have guilty of “treating the numbers.”  Beware new drugs proven to “treat the numbers” but not proven to reduce disease complications; there is a long list of medications that passed the former but failed the latter test.

For those unfamiliar with the history of warfarin, Karl Paul Link working at the University of Wisconsin set out to identify the hemorrhagic agent found in the spoiled hay and discovered warfarin. The name warfarin derives from Wisconsin Alumni Research Foundation.  Warfarin and similar compounds are still widely used as rodenticides—poisons used for controlling rats, mice,  and other rodents.  

The Sham of it all...

It’s official!  The American Academy of Neurology concludes that transcutaneous electric nerve stimulation (TENS) is not recommended for use in treating chronic low-back pain.  TENS is delivered using a small battery-operated generator connected to a set of electrodes. The generator, about the size of an IPOD, transmits a weak electric current through the electrodes, which are attached to the skin at the site of chronic pain or at other key points. But it took a while to come to the same conclusion that researchers reached in 1990.  In that year, an article appeared in the prestigious New England Journal of Medicine that compared TENS to sham TENS—the latter being an identical device, complete with lights that turned off and on, but did not produce electrical stimulation.  They found both equally effective. (NEJM 1990; 322:1627-1634)

But that isn’t the only sham story related to chronic low-back pain!  Sham acupuncture appears to work just as well as the real thing. Sham acupuncture involves placing needles in the back, but in the wrong locations.  It doesn’t seem to matter where the needles were placed. In article appearing in the Archives of Internal Medicine, researchers found that at 6 months, 47.6% of patients receiving real acupuncture and 44.2% receiving sham acupuncture demonstrated a significant improvement in back pain or function compared to 27.4% receiving conventional therapy.  No statistically significant difference between the real acupuncture  and sham acupuncture groups.  (Arch Int Med. 2009;169(9):858-66)

This raises important questions.  Would insurance companies pay for sham treatment?  And, if so, how does one become certified and credentialed to provide the treatment….?

SSRI Antidepressants Associated with Increased Mortality in Women

Serotonin Reuptake Inhibitors (SSRI) medications are best known by their brand names—Prozac, Paxil, Celexa, Lexapro, and Zoloft.  These are among the most prescribed medications in the US and are used to treat a wide range of psychiatric disorders including depression, anxiety, OCD, and PTSD.   SSRIs are believed to work through altering the balance of the neurotransmitter serotonin in the brain.   A number of researchers have raised concerns about SSRI prescribing practices, especially for women.

Smoller and associates from Massachusetts General Hospital analyzed mortality data from the Women’s Health Initiative (WHI) study, comparing mortality from all causes for women who consumed SSRIs with those who did not. A total of 136,293 postmenopausal women were involved in the WHI study. Their research findings appear in the December 14, 2009 edition of the Archives of Internal Medicine. The authors concluded that women using SSRIs had “a 45% increased relative risk of incidence stroke and a 32% increased risk of death in models stratified on propensity and adjusted for multiple covariates.”

Although this study found an association between SSRI use and increased mortality, it does not “prove” that SSRI medication caused cardiovascular or other diseases.  Depression itself or some other variable not considered in the study might have contributed to increased mortality. This study does, however, raise important concerns about SSRI use, especially because other treatments, such as cognitive behavioral therapy, are also effective in treating many of the same conditions for which SSRIs are prescribed.

Pharmaceutical advertisements oversimplify the complex neurobiology of psychiatric disorders in general and the role of serotonin in particular.  There are many serotonin receptor types, and most are found outside the central nervous system. Serotonin regulates numerous biological processes including cardiovascular function, bowel motility, sexual function, blood platelet regulation, and bladder control.  SSRIs have far ranging effects beyond the central nervous system and there has been scant research on the long-term effects of SSRI on these other systems. The findings of this study should not be dismissed out of hand.  It is plausible that SSRIs may be effective in relieving psychiatric symptoms but also having a deleterious effect on the cardiovascular or other organ systems.  The study also found increased mortality for women consuming another class of antidepressants—the tricyclics, many of which also affect serotonin levels through a different mechanism of action.

In the last few years, researchers have raised other concerns about SSRIs. Women who are pregnant or who are considering becoming pregnant should discuss alternatives to SSRI treatment with their physicians because SSRIs have been associated with birth defects, premature birth, and newborn pulmonary hypertension.  The use of SSRIs in teens has been associated with increased risk of suicide, prompting the FDA to include a “Black Box Warning” in the prescribing information. 

Smoller JW et al. Antidepressant use and risk of incident cardiovascular morbidity and mortality among postmenopausal women in the women's health initiative study. Arch Intern Med. 2009;169: 2128-213;2140-2141. 

CT Total Body Scanning, If you have the money, why not ...

We have all seen newspaper ads for radiology screening—often for CT Total Body scanning. The scans are painless, and, presumably, effective screening for heart disease, lung and other cancers. The ads suggest that scans can detect disease in their early, treatable phase. Not covered by insurance, many individual opt to pay for these test because it seems like a small cost relative to the benefit of early disease detection. 

The U.S. Preventive Services Task does not recommend CT scanning for early detection of diseases, and insurance will not pay for the service, but shouldn’t those who can afford Total Body scanning do what they can to reduce their risk of dying from cancer or coronary artery disease?  Public health experts have argued that these tests are of unproven benefit, but many potential Total Body scan customers are skeptical of expert advice. Those considering Total Body scanning have one proven reason to reconsider—the scan itself may cause cancer!

Two studies published in the Archives of Internal Medicine estimate the risk of developing cancer from CT scans. These studies highlight the fallacy inherent in the belief that more clinical information, more testing, and more technology inevitably leads to better health.  Each CT scan subjects patients to the equivalent of 30 to 442 chest x-rays depending on the type of CT scan, with CT angiography requiring the highest dose.  Berrington de González and colleagues estimated that there were 72 million CT scans performed in 2007. Based on this number and upon the know cancer risk from radiation exposure, they projected 29,000 cancers as a result of the CT scans done in 2007! Smith-Bindman and colleagues estimated that 1 in every 270 40-year-old women getting a single CT coronary angiogram would develop cancer!

If the risk of developing cancer is not sufficient to deter one from Total Body CT scans, consider this… CT scans often detect benign abnormalities that might have been better left undiscovered.  Not infrequently, one test begets another test.  As an example, a CT scan might find a poorly defined mass in the kidney or liver… probably an hemangioma (a benign blood vessel tumor). Under such circumstances, the Total Body Scan radiologist would likely send the report to the patient’s personal physician (who did not order the Total Body Scan). The physician, of course, is unlikely to recommend watchful waiting with a repeat scan in a number of months.  So, more tests are likely—possibly a MRI.  Sometimes, “lesions” need to be biopsied. And, sometimes, biopsies go wrong… internal bleeding being one of the more common complications.  So… the $1,000 Total Body Scan that seemed like such a good idea on face value turns out to increase the chance of developing cancer,  getting additional tests that weren’t necessary, and causing considerable worry (and, of course, the consternation of the physician who didn’t order the Total Body scan).  

In many ways, the problem of Total Body scanning is emblematic of one of the problems with the US healthcare system.  High tech sounds good.  High tech is expensive. High tech makes great advertising for hospitals. But the purported benefits of high tech are often unproven and, in some circumstances, just bad medicine. 

Berrington de González, A et al. Projected Cancer Risks From Computed Tomographic Scans Performed in the United States in 2007 Arch Intern Med. 2009;169(22):2071-2077.

Smith-Bindman, R et al. Radiation Dose Associated With Common Computed Tomography Examinations and the Associated Lifetime Attributable Risk of Cancer.  Arch Intern Med. 2009;169(22):2078-2086.

Yoga and Science

At the outset, I confess to being an avid yoga enthusiast—practicing daily and attending classes at least twice. I believe yoga is great exercise and has psychological benefits.

Yoga involves, among other things, breathing into the physical tension created by the various yoga poses while, at the same time, maintaining concentration and balance. Yoga is, in a way, a metaphor for dealing with the life’s challenges, and I believe that yoga practice does help relief anxiety and stress. According the National Center for Complementary and Alternative Medicine (NCCAM) “it is not fully known what changes occur in the body during yoga; whether they influence health; and if so, how. There is, however, growing evidence to suggest that yoga works to enhance stress-coping mechanisms and mind-body awareness. Research is under way to find out more about yoga's effects, and the diseases and conditions for which it may be most helpful.” That said, yoga instructors often provide what I consider unfounded, pseudo-medical explanations for health benefits.

What prompted me to write this blog was a pre-class discussion I had with an esteemed teacher (who also happens to be a RN and is respected by her students for her knowledge). Before the class, I noted that the instructor had covered her yoga mat with a blanket. It was cold outside and her yoga mat, as it turns out, was in her car. The blanket was intended to warm up the mat! Apparently, yoga mats do not comply with the laws of thermodynamics. In the course of yoga classes, I repeated hear references to physiology that, frankly, drive me crazy. Of course, with time and practice, I have learned to ignore them… most of the time. My favorites are as follows:

· “Inversions” (e.g. headstands) “reverse the blood flow”. Interesting…. When on stands on one’s head, according to yoga theory, blood flows backwards from veins to capillaries to arteries and, I assume, to the left side of the heart rather than the right!

· Yoga “twists” “wring out” toxins by squeezing the kidneys….apparently squishing the kidneys increases glomerular filtration rates the water is wrung out of a towel! Maybe yoga twists can help postpone the need for dialysis in patients with severe kidney disease.

· Trauma is “stored in the hip”. I have heard this fact stated hundreds of times. By stretching the ligaments around the hip joints, psychic trauma from current or, possibly, past lives can be relieved. Most scientists are, apparently, wasting their time looking at neurotransmitters in the limbic system.

· “Inversions” increase blood flow to the thyroid and parathyroid. Raising one’s feet above one’s head will increase venous blood flow (with a concomitant increase in central venous pressure). But will this cause an increase in arterial blood flow to these glands? And, if so, what difference would it make? Is there a health benefit to better blood flow to the thyroid? As any pathologist (or butcher) would tell you, the thyroid is a pretty vascular organ. Lack of blood flow rarely seems to be a problem.

· Breathing deeply and quickly “increases oxygen to the brain”, thus explaining why doing so results in dizziness. If this were the case, then breathing fast would be of particularly beneficial at the onset of a stroke! Take an aspirin and begin to pant! Unfortunately, rapid breathing does not increased oxygen delivery to tissues, but it does deregulate the respiratory chemistry be causing a decrease in CO2. The resulting change in pH causes dizziness and, sometimes, fainting—not desirable!

· “Breathe deeply into your kidneys and the adrenals”…. Does adding the description “kidneys and adrenals” result in deeper breathing? Is there an implied benefit for these organs by deep breathing? Will more oxygen reach them?

· The yogi “toe lock” (holding the great toe between fingers and thumb) is good for the pituitary gland. Which hormones are affected? Growth hormone? LH? If these levels are increased, male athletes could potentially save money on growth hormone and steroids but incorporating the toe lock into their workout regimens.

According to traditional yoga theory, regular practice will increase the “prana”—the essential life force. Proper breathing is considered a very important process as it is the most vital means of absorbing “prana” into the body. Amongst all the emotions, it is the negative emotions such as anxiety, suppressed anger and frustration that drain out the maximum amount of pranic energy. In theory, Yoga activates and corrects imbalances of energy contained in the seven “chakras” through proper breathing and assuming yoga poses. The original meaning of the word chakra was "wheel", derived from word for chariot wheels (a military innovation that Aryans brought to India). Of course, wheels have many symbolic meanings (e.g. the cycle of life, energy of the sun, etc.) The chakra are wheel-like vortices of energy believed to exist in a “subtle body” above the physical body. Scientific investigations using techniques such as magnetic resonance imaging (MRI), thermography, and electromyography have not demonstrated the existence of chakras, but, again, chakras are not believed to be part of the physical body itself.

Until science better determines how and why yoga works, instructors would be better served using traditional explanations rather than postulating positive effects through questionable physiologic mechanisms such as altered blood flow, oxygen concentrations, or improved organ function.

Namaste!