Is Vitamin D the "Missing Link" of Flu Prevention?

Vitamin D and Flu Prevention: Part 1

Influenza (the flu) is the poster-child of seasonal variability in an infectious disease. During "flu season" rates of influenza skyrocket, but in the warm, summer months the virus is seemingly dormant. I think that last bit does a particularly good job of beginning to elude to the commonly held beliefs surrounding the flu. Public officials tell us every year that this is going to be a bad year for the flu- perhaps the worst one yet. I think that most people conjure up an image of a virus that "attacks" every year, is defeated (fails to infect everyone), goes into hiding for the summer and makes itself bigger and better, and mounts an attack again the following year. It seems simple enough why people get sick- if you come into contact with enough germy people and if the virus is "bad" enough the virus will get you; it's only a matter of time. But what if the virus isn't the biggest variable in this equation- what if it's us?

There is a number of theories for what makes us more susceptible to infection in the winter. The start and end of the school year, the fall of absolute humidity in the winter months which dries out mucous membranes, seasonal patterns of behavior, temperature fluctuations, changes in viral transferability, and changes in host (human) immune function throughout the year all almost certainly play some role in influenza transmission [2]. Out of all of those reasons, however, one theory has risen above the rest in terms of answering unanswered questions (below) and promising research trials (to be discussed in Part 2).

Host (human) immune function is dependent on Vitamin D

Vitamin D is considered to be a hormone- a chemical that is made in one cell or gland (skin cells), released into the blood stream, and affects other cells in the body. Vitamin D is known to regulate at least 913 genes [3], including many that regulate immune function. Vitamin D is the major regulator of several antimicrobial peptides (AMPs) (you're body's in-house, broad spectrum antibiotics), namely cathelicidin and beta-defensin [3,4]. Among other functions, AMPs are known to protect the body's barrier surfaces (lungs, mouth and throat, gut) by creating a hostile antimicrobial shield [5]. This alone has tremendous implications in disease transferability! If the virus can not get past these barriers and get into the body it makes it tremendously difficult for it to make you sick. Vitamin D is also a key player in the innate immune system [3,5], which is the body's first, non-specific line of defense against pathogens. One way it does this is by enhancing TH3 cell function- T Helper cells that keep the rest of the immune system running smoothly. Fascinatingly, new research has shown that cells of the immune system and epithelium (barriers) are able to convert the non-active form of vitamin D into it's active metabolite [6]. This mechanism may further demonstrate the immune system's dependance on this modest little hormone.

Vitamin D as the "seasonal stimulus" answers many otherwise unanswerable questions about Influenza's odd behavior [5]

1. Why is Influenza both seasonal and ubiquitous (everywhere) and where is the virus between epidemics?
It is unlikely that the virus hides each summer and magically comes out in the winter. What's more likely is that the virus is around us (and in us) all year-round, but during times of enhanced immunity (sun exposure) we are able to fight it and remain asymptomatic.

2. Why are the epidemics so explosive?
As vitamin D levels begin to drop in the fall and winter months, so does our ability to fight infections. After a prolonged amount of time without sun exposure people's vitamin D levels will begin to fall, resulting in more and more people becoming increasingly more prone to infection. Once people's vitamin D levels drop below their tolerable threshold (which is most likely different from person to person), a subset of the population would find themselves suddenly susceptible to infection.

3. Why do epidemics end so abruptly?
It is likely that there is a sub-population of "good transmitters" within each population, which may be associated with each person's degree of Vitamin D deficiency. The depletion of this limited supply of good hosts most likely plays a large role in flu season's speedy resolution.

4. What explains the frequent coincidental timing of epidemics in countries with similar latitudes [5]? Why is the seasonal pattern of Influenza so weak or non-existent in equatorial regions [1]?
The peak of the last 25 epidemics in France and the USA occurred within a mean of four days of each other [5]. Similar latitudes likely follow a similar pattern (in both severity and seasonality) of impairments in innate immunity. This would also explain why regions closest to the equator experience fewer cases of influenza and seem to exhibit no pattern of seasonality [1].

5. Why is the serial interval so obscure?
The "serial interval" refers to the amount of time it takes for an infected person to make a well person sick. The serial interval has been shown for a number of other respiratory diseases, but has yet to be established for Influenza [5]. It appears that the presence of "good transmitters" among a population, who's infectious period is limited, makes this incredibly hard to measure for Influenza. The variation in Vitamin D status from one individual to another is likely one of many factors that seperates the "good transmitters" from the poor transmitters.

6. Why is the secondary attack rate so low?
For a  (supposedly) "highly contagious" virus such as Influenza, it's secondary attack rate is surprisingly low- about 15-20% at most, compared to 70% for measles and 58% for rhinovirus [5]. This is inconsistent with the idea that the virus sustains itself via regular sick-to-well transmission. The presence of a limited number of "good transmitters" as a result of vitamin D variation likely plays a role. Surely we've all known a person who always gets sick when there's a bug going around? It would be interesting to measure that person's vitamin D levels!

7. Why did epidemics in previous ages spread so rapidly, despite the lack of modern transportation?
"If Influenza were embedded in the population, only to erupt when impairments in innate immunity create a susceptible subpopulation, the disease would only give the appearance of spreading. Instead, it would appear in large segments of the population seasonally, and almost simultaneously, as long as good transmitters were available" [5].

8. Why are so few sickened by direct aerosol inoculation of influenza virus?
If the virus is highly infectious, one would expect most, if not all, people to fall ill when exposed to the virus. However, this is not the case. Even if the virus is sprayed directly into patient's eyes, nose and throat (I swear they really did this in 1918 and 1919) none of the volunteers became ill in any way. Other studies found similar results, where none or relatively few of the volunteers became sick after direct exposure to the virus. Once again, we must ask ourselves what makes one person susceptible and one person all but impervious to infection?

9. Why have influenza-related mortality and hospitalization rates significantly increased in the last three decades, despite profound increases in the rate of influenza vaccination?
Simply said, because vaccine manufacturers and researchers grossly overestimate the effectiveness of the flu vaccine every year. The flu vaccine lowers the incidence of the flu by 1.55%. If you want to know why I am so certain in saying so, please check out my previous blog posts on the flu vaccine here.

Check back soon for Part 2 of this series- I will be going over the current research on vitamin D as a means of preventing the flu.


Stay healthy out there, folks!

References:
[1] Juzeniene, Asta et al "The seasonality of pandemic and non-pandemic influenzas: the role of solar radiation and vitamin D" 2010 [PMID 21036090]
[2] Shaman, Jeffrey et al "Shortcomings of vitamin D-based model simulations of seasonal influenza" 2011 [PMID 3108988]
[3] Lang, PO "How important is vitamin D in preventing infections?" 2012 [PMID 23160915]
[4] Aranow, Cynthia et al "Vitamin D and the immune system" 2011 [PMID 3166406]
[5] Cannell, John et al "On the epidemiology of influenza" 2008 [PMID 2279112]
[6] Sundaram, Maria et al "Vitamin D and influenza" 2012 [PMID 3649720]

The Flu Vaccine: A Recap

I admit that last post was kind of intense, all be it a little controversial. A few readers didn't much care for the way I re-evaluated the numbers, even going as far as to say that I was lying. I am aware that not everybody is ready to be un-plugged from the matrix of mainstream medicine, but I certainly don't want anybody to walk away from this blog with a bad taste in their mouth. My goal is to empower you to take control of your health, stimulate thought and discussion, and open your eyes, ears and hearts to different opinions other than your own- not doop you into not getting a vaccine because of what I personally believe. Luckily a little syntax can go a long way, so lets see if I can't clarify and break that last post into bullet points.

• Looking at the results from the 2012 meta-analysis, the flu vaccine is about 56% effective. In other words, about half as many people get the flu when vaccinated according to the cited studies (4). However, this number does not take into account the numerous confounding variables that likely also contribute to so-called "vaccine effectiveness".

• However, the flu vaccine decreases incidence of the flu by 1.55%. That is, it lowers the odds of someone getting the flu from 2.73 to 1.18% (4).

• Researchers estimate that for every 100 people who get the vaccine, ONE case of influenza like illness (ILI) is prevented (10). Keep in mind, ILI may or may not be the actual flu, it simply means that someone feels like the flu.

• Other research estimates that for every 4,000 elderly people who receive the vaccine, ONE case of influenza related death is prevented (5). It is worth noting that it is the elderly who are most likely to get the flu and also account for approximately 90% of all influenza-related deaths.

• This is all assuming that confounding variables are not responsible for the benefit seen. However, there is ample evidence that indicates that part or ALL of the benefit seen in vaccination studies is due to variables other than vaccine effectiveness (1,2,4). For more on this, please see my previous article.

• It has been shown that the flu vaccine doesn't do anything to prevent community acquired pneumonia (9). This is important, because community acquired pneumonia causes approximately 34,000 of the 36,000 yearly deaths associated with the flu.

 

I would also like to point out that the flu vaccine is not benign. It, like anything else, can do harm. When you get a flu shot you are getting injected with things like mercury, formaldehyde, and aluminum salts (11). Just like we should look at the label for the foods we eat, so should we at least look at the ingredients of the vaccines we inject into our bodies. If you saw a food with formaldehyde in it would you still eat it? Would you feed it to your child?

Lastly, have you ever noticed the frequency with which the flu vaccine seems to make people sick? I'm not saying that it gives you the flu, but it seems like a lot of people just don't feel good after they get the flu shot. I know that word of mouth hardly has the street-cred of a meta-analysis, but its still something. After all, it was only simple hearsay that warned our ancestors to not eat the poisonous "death cap" mushroom a few thousand years ago... Imagine what would have happened if nobody had listened back then! If only Piers Morgan had listened to theflu vaccine nay-sayers..... (12)

I'm not saying we shouldn't try to prevent the flu. Nobody wants to get the flu, and it can be a serious illness. I just don't think that the flu shot is the safest, most effective or most logical way to do it. Instead of taking a disease-centered approach to care, I think that we'd have a better shot at preventing diseases if we focused on our health. For that matter, even if you do choose to get the flu shot I encourage you to still take an active roll in your health. Don't simply rely on the supposed passive immunity from the vaccine to save you, but take every step you can to ensure your whole-body health this flu season.


In health,

Nikki


References:
(1-10) Please see references from my previous post
(11) http://www.cdc.gov/vaccines/parents/vaccine-decision/ingredients.html
(12) http://2012thebigpicture.wordpress.com/2013/01/27/piers-morgan-falls-ill-days-after-public-flu-shot-with-dr-oz/

The Flu Vaccine: Your Best Shot at Preventing the Flu?

Once again, the flu season is well underway and there is no shortage of commercials, posters, billboards, and doctors telling us to get our flu shot. But is the flu shot really your best shot at preventing the flu? In part 1 of this series on flu prevention I hope to prove to you that the flu vaccine isn't as impressive as we have been led to believe. In the next post(s) I will discuss what has been proven in the research to naturally prevent the flu.

I know you're not all scientists, but a quick overview of the different forms of scientific research is necessary to fully appreciate the second half of this article. There are many types of research articles out there, and they all have varying degrees of abundance and credibility in the scientific community. For a more detailed description and explanation please see this website. For now all you need to know is that not all research is created equal. The most credible is the meta-analysis, followed by systemic reviews, randomized double-blind placebo studies, then cohort studies. Most of the research on the flu vaccine tends to be cohort studies, which are decent, but can still have a lot of flaws. Randomized control trials eliminate a lot of bias, but may still have issues as we will discuss below. Meta-analyses are considered to be the best because of their rigorous inclusion criteria. These studies compile information from many different articles, and more importantly, only the best articles make it into a meta-analysis.

As you will soon see, there are many different issues surrounding the debate of Influenza Vaccine Effectiveness. Issues like cohort (study group) selection bias, non-specific end points, and proper diagnosis of the flu can all stand in the way of an otherwise decent study, and will undoubtedly alter the reported numbers. Because it seems to be the most commonly recognized confounding variable in cohort studies, I will focus briefly on selection bias.

The term "selection bias" is a little bit of a misnomer in this case, because it is seen in cohort studies where the groups are not actually "selected" by the scientists. Rather, these studies follow two groups of people (those who got the vaccine and those who did not) and use the information to estimate how effective the vaccine is. The problem is that it's nearly impossible to account for other differences between the two groups of people. Factors such as health status, belief or disbelief in vaccine effectiveness, vaccine availability and possibly other unknown variables may all lead to the difference in behavior studied (i.e. the behavior to get the vaccine or to choose to not be vaccinated).

A great deal of skeptisism comes from what scientists are calling the "healthy user" effect, which means that the people who are getting vaccinated tend to be healthier, and therefore less likely to get the flu or die from it, than those who do not get the vaccine. This is the image of the ideal patient- someone who listens to their doctors advice; weather it be to eat more fiber, exercise, or get a vaccine [4]. One study examined this more in depth and compared several variables between the two groups: age, sex, the log of the insurance risk score, self-assessed health status, and presence of chronic diseases such as diabetes and heart disease. This study found a strong correlation between insurance risk score and self-assessed health status with risk of death, but more importantly they found a strong negative correlation between risk of death (poorer health prior to the flu season) and vaccine coverage. In other words, the more frail people, those who were the most likely to die with or without the flu, were among the least likely to get the flu shot, which undoubtedly skews the results of cohort studies in favor of higher vaccine effectiveness [5].

Aside from the patient's conscious choice there are also other factors that may create this effect. For example, vaccination is generally not recommended for the extremely frail or immuno-comprimised, a group that would be expected to have naturally higher hospitalization and death rates, who then get lumped into the "unvaccinated" group in a simple cohort study [4]. This is called a "frailty selection" [1]. In placebo controlled studies, it is considered unethical to include high-risk patients in such studies (it's not nice to give someone a placebo when there is a higher likelihood that the vaccine can save their life), so there is absolutely no high-quality (double blind, placebo controlled) data on the group that is theorized to benefit from vaccination the most [2].

In their paper, Simonsen et al [1] outlined criteria that can be used to detect such bias. The authors note, however, that it is easier to detect bias than to account for it and calculate exactly how much of the results are due to bias.

Seasonality. Think about it, the vaccine's ability to prevent death should be seasonal- only during the flu season when the virus is actually circulating. If there is a benefit outside of the flu season when the virus is not circulating, this is a strong indicator of a difference between the two groups. Several studies have identified a similar effect on all-cause mortality and hospitalization both during flu season and the off season, indicating an intrinsic difference between the ultimately immunized and non-immunized cohorts [1,6,7]. In 2008 Eurich et al demonstrated a 51% reduction in all cause mortality in pneumonia patients outside the flu season in those who would eventually get the flu shot- a number that is strikingly similar to what other groups report during the flu season [6]. The authors go on to say that this indicates that some or all of the benefit in mortality that is seen in cohort studies is likely due to confounding variables such as the healthy user effect [1].

Vaccine match. Each year the flu virus mutates, creating the supposed need to get the updated yearly flu shot. Each summer and fall, scientists have to try to predict which flu virus will be the predominant strain to make a vaccine against it. Some seasons end up being better matches than others. Such information can be found on the CDC website [8]. Logically, the effectiveness of the vaccine should fluctuate with how well the vaccine is matched to the circulating strain. However, this does not appear to be the case [1,4]. Below is a chart from a 2012 meta-analysis (remember, this means that the studies they use should be the best of the best) that shows how well the vaccine is matched and effectiveness [1]. As you can see, most of the studies from the years that were reported as being mismatched were reported to have the same or better effectiveness than other years. How can that possibly be?

The use of specific end points is important for obtaining accurate, clean results in a study. The more specific your end point (the thing you're measuring), the better the data you can obtain. Three things that are commonly used to describe flu vaccine effectiveness are all cause mortality, Influenza-like illness (someone says they have the flu), and laboratory confirmed influenza. Since people die from a lot of different things, even during the flu season, we would expect the vaccine's effectiveness at preventing all cause mortality to be relatively low. On the flip side, since the specific goal of the vaccine is to prevent the real flu (as opposed to ILI which may be the flu virus or something else), we would expect the vaccine's effectiveness here to be highest. On the contrary, current cohort evidence shows vaccine effectiveness estimates are highest (and implausibly large) for all cause mortality and lowest for laboratory confirmed influenza [1].

Cohort studies are most prone to bias because of the healthy-user effect, but even placebo controlled trials have their problems. Not only is the specificity of the end point being measured a concern, but the way those results are obtained may be an issue even in placebo controlled studies. Serology confirmed or laboratory confirmed influenza has been reported to skew results in favor of exaggerating vaccine effectiveness [2,4]. Culture confirmed influenza or better, vaccine-matched culture confirmed influenza seem to be the best in this regard, but the research in this area is sparse. Most studies look at all cause mortality, and many of the others look at laboratory confirmed infection, neither of which will give entirely accurate results.

Several authors have noted that the repeatedly reported 50% effectiveness against all cause mortality is simply not realistic. The flu only accounts for about 5% of all deaths in the winter, so "that the influenza vaccine can prevent ten times as many deaths as the disease itself causes is not plausible"[1]. Because influenza only contributes a small percentage to all cause mortality, it cannot be reasonably expected to do more than eliminate this excess. As I will show below, the real flaw lies in how that number, 50% is used, but there is another point to be made here. Several studies in the United States have tried to evaluate weather there has been a decrease in all cause mortality with increasing vaccination rates. In the last twenty years, since the flu vaccination rate among the elderly has soared from 15% to 65% there has not been a single study to has documented any change in hospital admission rates nor all cause mortality [6]. Similarly, studies failed to show an increase in mortality during the 1997-98 season, during which the vaccine was completely mismatched with the circulating strain [1].

Okay, here comes the really crazy part of this whole mess. For the time being, let's put aside all the stuff I just talked about and focus on the numbers- we'll assume that the data the studies are getting is actually reflective of what the vaccine is doing and that none of it is from confounding variables. We're not all statisticians here, but I think we can all do some basic 8th grade math. Let's solve this word problem:

100 people get the flu vaccine. Two of them get the flu. 100 other people do not get the vaccine. Four of them get the flu. How effective is the vaccine?

Okay, pencils down. Most of us would think through this problem like so, "We need to compare what percentage of each group got the flu. 2 percent versus 4 percent of each group got the flu. The vaccine was therefore 2% effective at preventing the flu. In other words, for every 100 people who got the flu vaccine, two less got the flu." What we just did was we calculated the absolute difference between the two groups- the percent difference. This is how people generally perceive percentages- we like to think of the number of people who's life would have been changed with the intervention. However, this is not how vaccine effectiveness is calculated. These studies calculate (and then report to us, the lay people) the relative difference between the two numbers. This is what it would be like for the example above, "We need to compare what percentage of each group got the flu. 2 percent versus 4 percent got the flu. 4 is twice as big as 2. The vaccine is therefore 50% effective."  Let that logic soak in for a minute or so. Yes, this is a perfectly legitimate way to compare these two numbers, two and four, but exactly what that percentage is comparing is rarely, if ever explained on flu vaccine posters. No wonder they're (and we) all are getting so confused! I think this is incredibly misleading. Let's look at the numbers from the studies cited by that 2012 meta-analysis again and compare the absolute values to their inflated relative values:

The way I see it, there has been an unintentional miscommunication between the science (research) world and the consumer world. We tend to see things how they relate to ourselves and we like to apply numbers to real life. I think when people see that the flu vaccine is 50% effective, they imagine it as "if I was 100% at risk, now that risk is only 50% which is pretty good". The reality is that most people's odds of getting the flu are already pretty low (2.73% odds without the vaccine if we use the numbers cited above), especially if you take care of yourself. What the vaccine does is it lowers your risk of getting the flu from 2.73% to 1.18%- which to you is only an overall difference in risk of 1.55%. Another way of looking at it is that you need to vaccinate 100 people to prevent ONE set of influenza symptoms [10]. As if that's not impressive enough, Fireman et al estimated that you would need to vaccinate 4,000 people to prevent one death from the flu in their elderly Kaiser Permanente cohort [5]. Again, this is the group of people theorized to need the vaccine the most and whom make up approximately 90% of influenza related deaths. Oh, and let's not forget that this doesn't even take into consideration the numerous confounding variables we talked about in the first half of the article, some of which have been shown to either partially or completely explain any benefit the vaccine has been shown to have. Call me crazy, but that doesn't sound nearly as impressive as the 50-70% effectiveness rates we typically hear about...

Not only is this misleading to the lay person, but researchers seem to be confused by their own statistics. Recall if you will, the authors who said that the 50% reduction in all cause mortality reported with the vaccine was unrealistic because the flu itself only accounts for about 5% of all winter deaths. They are trying to compare apples to oranges- you would have to back track and look at the absolute differences in order to compare these results to all cause mortality. Perhaps if they used the numbers from the Fireman et al study, 1 death prevented for every 4,000 vaccinated, that would make more sense. The kicker is that this wording was only used once toward the end of the article. If you read their abstract or their conclusion, however, even this group reported the vaccine effectiveness rate as 47% [5]!

It is worth noting that numerous studies have demonstrated that the vaccine is least effective in the two groups that are presumed to need it the most- children and the elderly [1,4].  In one trial the researchers estimate that the vaccine effectiveness drops from 75% to 23% between the ages of 65 and 70- a huge and important drop considering that 90% of all influenza deaths are in folks over the age of 65. There were no randomized clinical control trials that were good enough to meet inclusion criteria for the 2012 meta-analysis that showed TIV (trivalent influenza vaccine) effectiveness in people aged 2-17 or over 65 [4]. Only the live attenuated vaccine (LAIV) was shown to have any effect in the 65 years old plus crowd, but that vaccine is not approved for use in adults over 50 in the United States [4]. Perhaps most importantly for seniors, the influenza vaccine has been shown to do nothing to prevent community acquired pneumonia. Pneumonia is responsible for the vast majority of influenza-related deaths (approximately 34,000 of the 36,000 deaths) each year [9], so this certainly doesn't lend much credibility to those estimates on decreasing all cause mortality.


I think it's safe to say at this point that there are a LOT of things to consider when it comes to this body of research. There are numerous confounding variables that may either partially or completely account for the reported effectiveness of the vaccine, "effectiveness" can mean anything from preventing death to preventing the flu, there is a lack of solid evidence that the vaccine works at all in the populations that supposedly need it the most, and the method of reporting the vaccine effectiveness is misleading at best. There are other issues that simply could not make it into this post such as the ingredients in the vaccine, side effects, politics, marketing, and conflicts of interest with funding sources. But all things said, I can not legally tell you whether or not you should get the flu shot. Whether you choose to get the vaccine or not is your personal choice, and I understand that there are a lot of factors that do, and should, go into this decision. All I can hope to do is educate you so that you can make the best decision for you and your family. I personally think I have a better shot (pun!) at preventing the flu if I keep myself healthy... especially when you take the unimpressive results from the research into consideration.

Even after all that, we still haven't gotten to talk about what actually causes the flu! I know what you're thinking, the influenza virus causes the flu. But the reality is that it is predominantly your health as host that determines weather or not a virus will successfully make you sick. Surely we have all lived with someone who has gotten sick, yet did not get sick ourselves. There had to have been a reason why you didn't get sick, and it surely wasn't from lack of exposure. Next blog post we're going to talk about what actually causes the flu, as well as what natural things you can do to prevent it. Spoiler alert- there is a vitamin out there that kicks flu vaccine butt at preventing the flu!

Stay healthy,

Nikki Cyr


References:
[1] Simonsen, L. Mortality benefits of influenza vaccination in elderly people: an ongoing controversy. Lancet Infectious Dis 2007;7:658-66
[2] Jackson, L. Safety, efficacy and immunogenicity of an inactivated influenza vaccine in healthy adults: a randomized, placebo-controlled trial over two influenza seasons. British Medical Journal Infectious Diseases 2010, 10:71
[3] Lang, P. Effectiveness of influenza vaccine in aging and older adults: comprehensive analysis of the evidence. Clinical Interventions in Aging 2012:7; 55-64
[4] Osterholm, M. Efficacy and effectiveness of influenza vaccines: a systemic review and meta-analysis. Lancet Infectious Disease 2012; 12: 36-44
[5] Fireman, B. Influenza vaccination and mortality: Differentiating vaccine effects from bias. American Journal of Epidemiology 2009;170:650-656
[6] Eurich D. Mortality reduction with influenza vaccine in patients with pneumonia outside "flu" season. American Journal of Respiratory Care Medicine 2008;178:527-533
[7] Hottes, T. Influenza vaccine effectiveness in the elderly based on administrative databases: change in immunization habit as a marker for bias. PLoS ONE 6970: e22618
[8] http://www.cdc.gov/flu/pastseasons/1112season.htm
[9]  Jackson. Influenza vaccination and risk of community acquired pneumonia in immunocompetent elderly people: a population-based nested case-control study. 2008;372:398-405
[10] Jefferson, T. Vaccination for preventing influenza in healthy adults. Cochrane database of systemic reviews; 8 article CDOO4879

Metals That Might Make You Mental

I've said it once. I've said it a million times. They haven't found a cure for Alzheimer's Disease because they don't know what causes Alzheimer's Disease. They don't know the cause of AD because there is no cause, per say. There are genes that make you more prone to the disease (such as ApoE), but there is no AD gene. There is no vitamin deficiency, toxicity, gene or one thing that causes AD. Instead, it appears that AD is a multifactorial disease that is caused by a different mix of things in each individual person. The only true cause that continues to have overwhelming evidence confirming it's role in causation of AD is inflammation... But that's where the multifactorial thing comes in. Weather it be a bad diet, head injury, drugs, infections, thoughts, toxins or autoimmunity, many things cause inflammation. Therefore, many things can contribute to one developing Alzheimer's Disease. The Alzhimer's Disease brain is a brain on fire, and research continually shows us that the fire starts many, many years before we see the smoke. There is no magic bullet to prevent Alzheimer's Disease; you just have to live a healthy life.

Everybody has heard of heavy metals. The bad guys of the periodic table, heavy metals such as mercury and lead have been associated with a wide range of diseases and disorders. But what about other metals? What about the metals we thought all along were good for us? In comes Iron (Fe) and Copper (Cu), two transition metals that may be new culprits in the AD puzzle and inflammation in general. But everybody knows we need iron to make hemoglobin, so having too much couldn't possibly be a bad thing, right? Wrong. The type of Iron or Copper dictates how it functions in the body, and having too much of the "bad" kind can wreak all sorts of havoc on the body.

Transition metals are unique because they exhibit two or more oxidant states (for example, Fe+2 and Fe+3). This is what makes able to participate in chemical reactions and makes them particularly useful in day to day bodily functions. This characteristic also makes them remarkably able to bind with stuff we don't want them to bind to and create free radicals. Free radicals like the hydroxyl ion are then able to scamper about the body binding to molecules and altering their function... This is the hallmark of inflammation- free radical damage that alters the body's normal molecules, and subsequently alters the function of those molecules.

For simplicity's sake, there are two basic types of metals: free metals (inorganic) and metals that are bound to other stuff (organic). Weather or not these metal ions are bound to a molecule (such as a protein) will affect how they are absorbed and processed by the body. Organic Copper and Iron compounds are absorbed a little slower by the intestinal tract, but more importantly they are processed differently than their inorganic brethren. Food Copper (and Iron) must go through additional processing in the liver before it is allowed into systemic circulation (the blood stream). Typically the body keeps most of it's Copper bound to proteins and keeps the more unstable, inflammatory free Copper to a minimum (5-15% total Cu in the blood). When inorganic Copper is absorbed it immediately contributes to the free Copper pool in the blood steam, bypassing the liver and increasing the risk of inorganic Copper induced oxidative stress [1]. Similar is true of Iron's story.

The proposed mechanisms of how inorganic Copper and Iron contribute to the inflammation in AD are numerous, but here are a few.

Copper has been shown to bind with homocysteine (an inflammatory molecule that is related to one's intake of B vitamins) and increase the oxidation of LDL- the so-called "bad" cholesterol [1, 2]. Cu, unlike Zinc, Nickel, Aluminum, or Cadmium, has been shown to compromise the stability of Ubiquitin. The Ubiquitin-Proteasome System (UPS.. haha) is the main pathway by which we eliminate misfolded proteins from our cells such as the notorious Beta Amyloid of Alzheimer's Disease and the Lewy bodies that are seen in Parkinson's Disease [5]. This may result in decreased clearance of these proteins in the brain, eventually leading to a build-up, cellular toxicity and death. Even the so-called AD gene may be related to Cu metabolism! The three different ApoE Alleles differ in the number of cysteine binding sites they posses- the part of the molecule that is able to bind to Copper. ApoE 2 has two binding sites, ApoE3 has one and ApoE 4 has none. This correlates with the risk of AD associated with each of those alleles (2 is protective against AD, 3 is neutral and 4 increases your risk). It has now been postulated that the risk associated with the ApoE alleles is due to ApoE 4's inability to bind and remove Copper from the brain [2].

Like Copper, Iron is necissary for human life, but an excess of inorganic Iron may be one of the inflammatory triggers in the AD cascade. Several studies have shown that Fe accumulates in Beta Amyloid plaques [3]. Not only that, but the presence of Iron during plaque formation not only increases the synthesis of Beta Amyloid by it's interaction with PACE, but it has been shown to favor the more toxic form of the plaques [4].

As in all things in life, your current inflammatory status will play a role in how you handle further stressors. Inflammation disrupts the blood brain barrier (BBB) and alters it's ability to regulate the transport of Fe to and from the brain [4]. HAMP, the gene that is responsible for the production of Hepcidin (THE Iron homeostasis hormone in our bodies) is directly influenced by inflammatory cytokines such as IL-1B and IL-6 [4]. Similarly, the mechanism I mentioned above of how Copper binds to homocysteine to produce inflammation would probably not be that big of a deal if you didn't have high homocysteine levels in the first place!

So what can we do to avoid the damage caused by inorganic Copper and Iron?

1. Decrease your inflammatory burden. I've said it once. I've said it a thousand times. This is highly individual, since no two of us have the same health problems. Weather it be being overweight, not exercising, a crappy diet, diabetes, gastrointestinal issues, an autoimmune disease, or whathaveyou, get healthier. If you're not inflamed it appears that these pesky metals won't hurt you as much.

2. Avoid inorganic Copper and Iron. Brewer et al [1] and several others have identified the two major sources of inorganic Copper and Iron as being Copper in our drinking water from Copper pluming and multivitamins (like Centrum). Interestingly, Brewer et al [2] points out in his paper that all of the industrialized countries are dealing with increased rates of AD- Except Japan. This is noteworthy, because Japan is the only industrialized country that does not use Copper pluming. In contrast, about 85% of US homes have Copper pluming [2]. Here's what you can do to minimize the amount of Copper that leaches into your water and avoid inorganic Copper and Iron:
     A. Filter your water. Brita.com does state that their filters filter Copper, but I can not say to what extent. Reverse osmosis is the best at
     filtering things like Cu and Fe, but is more expensive.
     B. Do not get hot water from the tap- Hot water will leach more Cu from the pipes than cold water- Warm the water after it comes out of the
     faucet.
     C. Check the acidity of your water. The more acidic your water, the more it will etch the Copper pipes.
     D. Avoid multivitamins like Centrum. They look like a big ol' piece of metal that they painted red anyway, so who are we fooling when we
     take those? There is no substitute for the vitamins and minerals you get from a healthy diet. Period.

 3. Zinc has been shown to lower levels of free Copper in the blood [2], so making sure you have adequate Zinc levels may be a good idea if you think you're at risk of ingesting too much Copper (perhaps people who have really acidic water at home and can not afford to install a reverse osmosis system).

Healthfully yours,

Nikki

References:
[1] Brewer, G. Risks of Copper and Iron Toxicity during Aging in Humans. Chem Res Toxicol 2010, 23, 319-326 (PMID 19968254)
[2] Brewer, G. Copper Toxicity in Alzheimer's Disease: Cognitive Loss from Ingestion of Inorganic Copper. J of trace elements in medicine and biology 26 (2012) 89-92. (PMID 22673823)
[3] Batista-Nascimento, L. et al. Iron and Neurodegeneration: From Cellular Homeostasis to Disease. Oxidative Medicine and Cellular Longevity, May 2012 (PMID 22701145)
[4] Mesquita, S. et al. Modulation of Iron Metabolism in Aging in Alzheimer's Disease: Relevance of the Choroid Plexus. Frontiers in Cellular Neurosci. May 2012 (PMID 22661928)
[5] Arnesano, F. et al. Copper-Triggered Addregation of Ubiquitin. PLoS ONE 2009 Sept 16; 4(9) e7052 (PMID 19756145)

A New Way to "Think Pink"

Ah, October. A month for trick or treating, crisp fall weather, carving pumpkins, apple cider, and pink. Yes, October is National Breast Cancer Awareness Month, and of all the months dedicated to a disease this one is the most prominent every year. You couldn't forget this one even if you tried, with all the pink-clad fundraisers and the wide array of pink products that hit the shelves this time of year.

I always thought the idea of having an "awareness month" for a disease such as breast cancer was a little weird. I'm fairly certain that we've all heard of breast cancer, so making us "aware" of the disease seems a bit redundant. Of course the month is really much less about actual awareness and more about fundraising, and therein lies the issue I take with this month.

If you look at the participating products in the "save lids to save lives" list [1] you'll notice that they're not the most healthy products. Actually, they are downright unhealthy. Yoplait yogurt, Totino's pizza rolls, Pillsbury cookies and cinnamon rolls, gummy snacks and cereal are just a few to grace the list... but this begs an important question: What's the point of raising awareness and money for cancer when the very products you buy to support the cause will (probably) give you the disease?? Clearly the people who approved these foods either don't understand human health or are more concerned with lining their pocketbooks than anything else. Call me a cynic, but I think the pink thing is yet another marketing ploy to encourage people to buy these unhealthy products. If you want to give money to cancer research go right ahead, but do yourself a favor and just write Susan Koman a check instead of buying this crap.

Furthermore, why are we raising money for a cure and not talking about prevention? I would be much more on-board with this whole "disease month" thing if they were about prevention. So instead of buying those cinnamon rolls and raising what is likely pennies for research to find a cure, go for a run and make sure you never need a cure.

When I get into practice (soon!) I plan on doing workshops and programs geared toward breast cancer prevention during the month of October, so stay tuned next year. Let's stop thinking in their box (big pharma and it's box of drugs) and create a new one, shall we?

Inspired by the need for change,

Nikki

References:
[1] https://savelidstosavelives.com/ParticipatingProducts