Inflammation and Oxidation

Inflammation and oxidation contribute to many, if not most, diseases.

Based on this observation one would suspect that anti-inflammatories and antioxidants should prevent many diseases. Indeed, there is excellent data that anti-inflammatories can help prevent many diseases. However, support for antioxidants is more limited.

First, antioxidants.

There are a number of antioxidants that one must consume (e.g., vitamin E, vitamin C, zinc, and selenium). There is a lot of mileage in making sure that one is not deficient in any of these antioxidants. However, there is decent evidence that, in general, after sufficiency is attained, more is not better.

The body also has a number of in-house antioxidants, known as endogenous antioxidants (e.g., superoxide dismutase, glutathione peroxidase, alpha lipoic acid, catalase and coenzyme Q10). Many external, or exogenous, antioxidants (like the vitamins and minerals mentioned above) are necessary to maintain proper levels of these all-important endogenous antioxidants. Moreover, many exogenous antioxidants also happen to have other biological effects aside from reducing oxidation (e.g., some have anti-inflammatory effects and some are polyphenols with diverse effects)

And, that might very well be all there is to exogenous antioxidants -- they're important, but perhaps not because of their (direct) capacity to reduce oxidation...

And now, inflammation.

Inflammation generally starts with injury (e.g., acid or bile injury in the case of esophagitis). The body responds to an injury by sending lots of blood to the area to address the underlying problem. The body's response is modulated by a cascade of signaling molecules designed to cause the inflammatory reaction.

On a molecular level, the signaling cascade starts with omega 3 and omega 6 fatty-acids. These fatty-acids, made from dietary polyunsaturated fat, are turned into signaling molecules called eicosanoids. Two families of enzymes catalyze fatty acid oxygenation to produce the eicosanoids: (1) cyclooxygenase, or COX, which generates the prostanoids (Cox-2 generates PGE2) and (2) lipoxygensase, or LOX ( 5-LOX generates the leukotrienes).

It turns out (and this is a bit of a simplification) that there are two broad types of prostanoids and leukotrienes: (1) inflammatory prostanoids and leukotrienes and (2) anti-inflammatory prostanoids and leukotrienes. Significantly, omega 6 fatty acids are the precursors to the inflammatory prostanoids and leukotrines while omega 3 fatty acids are the precursors to the anti-inflammatory prostanoids and leukotrines.

Almost all modern people eat way more omega 6 than omega 3 fatty acid (some eating 50 times more). Unfortunately for us, most people for the last 2 million years ate a fairly even ratio. Sounds like trouble...

With such an over-abundance of omega 6 in our tissue, there generally aren't enough omega 3 precursors present to be made into anti-inflammatory signaling molecules. Chronic inflammation, inflammation that outlives its biological purpose, seems to be the result.

Tissue highly unsaturated fat (omega 3 and omega 6) has a two-year half-life on average. That means that it takes two years for your body to replace half this fat in your body. In addition, omega 6 oil is ubiquitous in our food supply (vegetable oils, corn/soy fed animal, nuts & seeds). Thus, replacing all that tissue omega 6 with tissue omega 3s takes a long time and is hard to do. That said, I am currently in the process of doing it because it is the actual cure rather than the band aid.

In the meantime, NSAIDs can help to stop chronic inflammation by inhibiting the Cox-2 enzyme and/or by inhibiting the 5-Lox enzyme (by the way, it might be ideal to inhibit both Cox-2 and 5-Lox at the same time). Turmeric, ginger, green tea, french pine bark, and numerous other natural compounds inhibit both enzymes. In addition, aspirin is a potent inhibitor Cox enzymes and boswellia is a potent inhibitor of 5-Lox.

In the context of the chemoprevention of esophageal cancer in people with Barrett's esophagus, there is very good epidemiological data for aspirin. Indeed, aspirin is currently the subject of a placebo-controlled trial in England, which should produce some preliminary data in 2011. However, aspirin's effect on cancer progression, if any, might be due to mechanisms other than Cox-2 inhibition (as suggested by a trial, albeit a small & short one, in which selective a Cox-2 inhibitor didn't perform so well). For instance, aspirin also promotes cellular adhesion. (I believe that the authors of the U.K. trial also share my suspicions about aspirin as the dose they are using, 300mg, is well in excess of the dose required to effectively inhibit Cox-2, suggesting they are interested in exploring some of the other benefits of aspirin.)

I know this sounds like a broken record, but vitamin D also promotes cellular adhesion, probably better than does aspirin.

Incomplete Reversal of Barrett's Esophagus

Does ablation of non-dysplastic Barrett's esophagus make sense?

According to one recent study and another ten-year old study, squamous islands, created during the incomplete ablation of Barrett's esophagus, may still be genomically unstable and prone to carcinogenesis.

The creation of squamous islands (i.e., islands of normal esophageal cells in the sea of Barrett's esophagus cells) can occur as a result of prolonged PPI therapy. The simplest hypothesis is that normal squamous cells grow over or grow out from under the Barrett's cells once conditions in the esophagus return to normal due to acid suppression. The potential creation of squamous islands is promoted as one of the successes of PPI therapy.

However, a study way back in 1999 found that these squamous islands possess abnormal biomarkers (e.g., Ki-67, p53 abnormalities) that suggest genomic instability and continued risk for cancer progression. I am not aware of any follow up studies showing that such squamous islands progress to cancer at higher rates than other tissue, and suspect the implications of this finding are not fully understood yet.

Interestingly, the recent study cited above showed that incomplete photodynamic abaltion produces similar results -- abnormal biomarkers, including Ki-67, cyclooxygenase-2 (COX-2), and p53 staining.

The moral of the story is that if you get photodynamic therapy, don't be one of the 30%-50% of people whose doctors do it wrong... The more serious moral of the study, is that it might not be a good idea to get photodynamic ablation unless you already have dysplasia.

I just don't know whether the 1999 finding is a good enough reason to stop PPI therapy. I guess I have some faith that, since this has been known for 10 years, somebody would have noticed if those "lucky" people with squamous islands were dropping dead faster than those without. Perhaps the abnormal biomarkers are just a temporary sign of genomic instability in the good sense -- i.e., caused by the reversion to neo-epithelial cells -- and not a genomic instability that leads to cancer?

In any case, I suspect that eating and supplementing in a manner that promotes genomic stability should help. Vitamin D seems to be one powerful weapon in this fight. There are others that I will discuss in future posts.

Image from here.

Pure L-Theanine

As I mentioned in an earlier post, theanine, an amino acid found in green tea, should help reduce reflux by increasing GABA levels in the central nervous system. Because green tea also has caffeine, which inhibits GABA release, I decided to take pure L-theanine, available in pill form, to see if it would help my reflux.

I took 100mg L-theanine about 5 times (when I had reflux) over a period of two weeks. I stopped the experiment early because L-theanine seems to make me anxious and/or give me heart palpitations. It's not supposed to do that at all, so I'm not sure it wasn't just coincidence or imaginary. But, to be safe, no more L-theanine for me. Besides, based on my limited experience with it, I don't think it helped my reflux that much.

I'm going to move away from anti-reflux measures for a little while to focus on some core Barrett's esophagus chemopreventation strategies. I will return to anti-reflux measure after I complete a few more experiments. Stay tuned.

Does Reflux Matter?

Most cases of esophageal adenocarcinoma start with Barrett's esophagus and most cases of Barrett's esophagus start with reflux. Does it follow that stopping reflux can halt the cancerous progression of Barrett's esophagus? I'm not so sure.

As you would expect, reflux isn't made up of just acid. It includes partially digested food, bacteria, stomach acid, and bile, among other constituents. And, it seems that both acid and bile reflux play important roles in the development of Barrett's esophagus.

It is not as clear that reflux causes Barrett's esophagus to progress to cancer as it is that reflux causes Barrett's esophagus to develop in the first place. For example, surgical correction of the lower esophageal sphincter doesn't seem to be better than acid suppression at reducing the risk cancer in people with Barrett's esophagus. Likewise, consumption of substances, like alcohol, that increase reflux don't seem to be significantly associated with the progression of Barrett's esophagus to cancer. On the other hand, excessive consumption of alcohol in early-life (presumably before the development of Barrett's esophagus) is strongly associated with having Barrett's esophagus later in life.

One manner in which reflux may contribute to the cancerous progression of Barrett's esophagus is by causing damage to the esophagus that results in chronic inflammation. Acid suppression seems to reduce this chronic inflammation, which is why I take a PPI every day. There are different viewpoints on whether acid suppression is cost-effective chemoprevention for esophageal adenocarcinoma - for example, see this. Having studied both sides of the debate, I suspect it's wise to suppress acid at least enough to control chronic inflammation. Unfortunately, there have been no placebo controlled trials on the efficacy of PPIs for chemoprevention of esophageal adenocarcinoma, so we don't know for sure and are unlikely to know for some time.

Beyond contributing to chronic inflammation, I suspect that reflux plays a relatively minor role in the progression of Barrett's esophagus to cancer. Instead, my guess is that once a person gets Barrett's esophagus, the Barrett's cells that have formed are on march towards cancer that is principally modulated by (i) inflammation, (ii) diminished genetic stability/cellular adhesion, and (iii) poor immune response.

That said, I still worry about reflux for three reasons:

1. Since I only have short segment Barrett's esophagus (about 1 cm), there are still many more cells in the vicinity of my dysfunctional LES that could "go rogue" (i.e., become Barrett's esophagus cells). Since the the chance of progressing to cancer seems to depend, to some extent, of the amount of Barrett's cells one has, I would like to have fewer Barrett's cells if possible.

2. Acid suppression doesn't do much to prevent bile reflux, and bile reflux may contribute to inflammation.

3. There's a chance that reflux is a player (beyond its effect on inflammation) in the progression of esophageal cancer after all.

Green Tea; Theanine, Caffeine, and GABA

Among its many health benefits for people with Barrett's esophagus, green tea also seems to reduce reflux by tightening the lower esophageal sphincter. Green tea's effect on reflux is caused by the caffeine and theanine in it, both of which affect the CNS control of the LES. Caffeine decreases the amount of GABA in the Vagus nerve while theanine increases the amount. More GABA in the Vagus nerve produces a tighter LES, and a tighter LES produces less reflux. Since the theanine in green tea has a more potent effect on GABA than caffeine, green tea should, in general, reduce reflux. Indeed, it does just that for me.

Since caffeine undoes some of theanine's good deeds, it might be nice, especially at night, to brew a cup of high-theanine, low-caffeine tea. I know that most of the caffeine is released from tea leaves in the first 30 seconds or so, but I can't find reliable information on the release of theanine from tea leaves. Decaffeinated green tea may offer a solution as it seems that supercritical CO2 decaffeination (a method used for all organic decaf green teas), leaves in most of the theanine. Also, I believe there's more theanine in high quality loose leaf tea than in teabag tea, so I would generally recommend loose leaf teas.

A post on theanine supplements coming soon....

Central control of reflux; the Vagus nerve

The body has two safeguards against reflux, the diaphragmatic sphincter and the lower esophageal sphincter. Both are supposed to remain shut unless you swallow, burp, or vomit, but sometimes they malfunction and cause reflux. Typically, there are two kinds of malfunctions: (i) transient lower esophageal sphincter relaxations and (ii) weakness in one or both of the sphincters.

The first type of malfunction, transient lower esophageal sphincter relaxations, is basically a brief (i.e., a couple of seconds long) relaxation of the sphincters. Many things can cause these relaxations, including stomach distention, certain food items, and stress. Transient esophageal relaxations are likely the cause of most cases of GERD.

The second type of malfunction, sphincter weakness, is a more prolonged defect in one or both sphincters. Many things can cause such sphincter weakness, including stomach distention, abdominal pressure (such as from weight lifting or straining to go the bathroom), certain food items, certain medications, irritation of the esophagus, and stress. This type of malfunction seems to result in more serious GERD, especially when lying down at night.

Both types of malfunctions also seem to be under some form of central nervous system control via the Vagus nerve, with the result that reflux may be modulated, to some extent, by tweaking the neurotransmitters and receptors of the Vagus nerve. As I mentioned recently, cisapride seems to tighten esophageal sphincter pressure, likely by increasing the amount of acetlycholine in the Vagus nerve. Unfortunately for cisapride (and many other drugs in its class), it also increases the amount of acetlycholine elsewhere and can lead to some bad side effects (like cardiac arrhythmias).

Transient lower esophageal sphincter relaxations seem to be modulated by wide vareity of neurotranmitters, including GABA, glutamate, nitic oxide, and substance P, Cannabinoids. Melatonin, zinc, cholecystokinin, gastrin, atropine, and opioids may also play a role.

As you can see, there are many potential targets that could affect reflux. I will experiment with a number of substances that I know to affect one or more of these targets and that I consider safe. I am not interested in gambling (especially against the odds), so I am confining myself to only those foods & supplements that have been used well for long periods of time by large numbers of people. Results from these experiments will be the subject of numerous future blog posts.

Anatomical picture above is from here.

Swine Flu

In addition to having a regimen for Barrett's esophagus, I also have a regimen for swine flu. So far, not that much is known about prevention of swine flu, so my swine flu regimen is based on extrapolations from other data (i.e., studies about colds & regular flus or the immune system generally) . Nothing below is proven to prevent or cure swine flu and I am not selling anything whatsoever.

The goal is to promote the immune system while inhibiting a cytokine storm. If you have any questions about why I've included a particular item in my swine flu regimen, feel free to ask because I don't plan on explaining the regimen in future blog posts.

Over the past two days, I have conducted a test run for my anti-swine flu regimen. The timing was perfect as I had just started to feel the first effects of my wife’s cold. However, after unleashing the full power of my regimen, I emerged unscathed while she is still slightly sick.

Here's the regimen:
vitamin D 5000IU
vitamin C 6 grams (500mg every half hour)
green tea 5 cups
coconut oil 2 tablespoons
selenium 50 mcgs
zinc 25 mg
resveratrol 250mg
quercetin 200mg
sulforaphane 100mg
vitamin E 30IU
whey 2 tablespoons
glutamine 4500 mg
heavy cream 2 cups
turmeric 400mg
pomegranate extract 2 tablespoons
melatonin 6 mg
cimetidine (tagamet) 800mg (in divided doses)
probiotics
magnesium
I also use a neti pot.