Intestinal mucosal damage caused by NSAIDs Role of bile salt

[mle_ii]

Back to bile again... seems it has a tie in with NSAIDs.

http://www.ncbi.nlm.nih.gov/entrez/quer ... med_DocSum
Intestinal mucosal damage caused by non-steroidal anti-inflammatory drugs: Role of bile salts.

The strong analgesic, anti-inflammatory effects of non-steroidal anti-inflammatory drugs (NSAIDs) are hampered by high occurrence of gastrointestinal side effects. Therapeutic actions of NSAIDs result from cyclooxygenase (COX) enzymes inhibition with reduced synthesis of prostaglandins, major modulators of inflammation. Since prostaglandins also regulate key events in gut homeostasis -mucosal secretion, blood flow, epithelial regeneration - COX inhibition has been accepted as the reason for NSAID gastrointestinal toxicity. Several findings challenge this theory: first, intestinal damage by NSAIDs occurs also in COX-1 knockout mice, demonstrating that topical (non-prostaglandin mediated) mechanisms are involved; second, no correlation is found in vivo between the extent of intestinal injury and the degree of inhibition of prostaglandin synthesis; third, bile flow interruption in animal models completely prevents intestinal damage by parenterally administered NSAIDs. What is in bile that could play a role in NSAID toxicity? This timely review will critically discuss the role of bile salts in NSAID-dependent gut damage.

I read the entire article. It seems that NSAIDs cause bile to become more toxic and thus does damage to the tissue it comes into contact with. So this would mean damage to anywhere the bile cycles through, so starting at the gallbladder, we go into the small intestine, in the small intestine we go into the ileum where it's reabsorbed into the bloodstream, then makes it way to the liver and the back to the gallbladder. If the ileum is dammaged or not absorbing enough bile the bile goes into the colon where it is either absorbed there (via multiple mechanisms) again into the bloodstream as above or it continues on and exits the body via the stool.

So we've got this toxic bile recirculating through our GI systems. Can't be good. And since the body only really responds to too much or too little bile then it just keeps recirculating. I'm guessing that is until too much damage is done. Might this be the same damage occuring to some of the folks here who've had their gallbladders removed?

An interesting tidbit is that normally the body takes care of too much bile by not absorbing it. It senses it via the FXR receptor. I think I remember reading that glucocorticoids and Vitamin D also act on this same receptor. Though I think that they caused recirculation of the bile rather than letting it go out. Gotta look that up again and write it down somewhere.

Also, I'm wondering if the right bacteria might be good at making this bile less toxic (perhaps that's why not everyone gets dammage done). It also appears that mucus inhibits this damage due to creating a barrier, heck even probiotics would, I assume, also be a barrier to this. Perhaps even calcium is involved here as well via binding to the bile.

I also wonder if other things besides NSAIDs increase the toxicity of bile. I believe so but I can't remember what. Though some bad bacteria I think was one of them.

Thanks,
Mike

[tex]

Mike,

I agree that NSAIDs do bad things in combination with bile, but I don't believe that anyone without a gallbladder is necessarily headed for trouble, because of excess bile in circulation. I get the impression from reading, that you're sort of assuming that excess bile production is bad. Actually, it's a vital part of our digestive process, and unless something is seriously wrong, the liver produces bile in response to the ingestion of food, (not just arbitrarily), so there shouldn't normally be a significant overproduction problem. After all, part of it is used to flush out certain body wastes, from the liver, (in fact, bilirubin is what gives bile it's color), so if it's not flowing on a regular basis, we're in serious trouble. Unless bile reaches the colon, peristaltic action may even be hampered, which could cause slow motility, and/or constipation. Are you sure that a high percentage of it is recirculated? I would think that most of any excess would be purged, rather than recirculated.

http://www.hepcuk.info/data/usercontent ... 20Bile.asp

Tex

[mle_ii]

Mike,

I agree that NSAIDs do bad things in combination with bile, but I don't believe that anyone without a gallbladder is necessarily headed for trouble, because of excess bile in circulation. I get the impression from reading, that you're sort of assuming that excess bile production is bad. Actually, it's a vital part of our digestive process, and unless something is seriously wrong, the liver produces bile in response to the ingestion of food, (not just arbitrarily), so there shouldn't normally be a significant overproduction problem. After all, part of it is used to flush out certain body wastes, from the liver, (in fact, bilirubin is what gives bile it's color), so if it's not flowing on a regular basis, we're in serious trouble. Unless bile reaches the colon, peristaltic action may even be hampered, which could cause slow motility, and/or constipation. Are you sure that a high percentage of it is recirculated? I would think that most of any excess would be purged, rather than recirculated.

http://www.hepcuk.info/data/usercontent ... 20Bile.asp

Tex

Sorry for the confusion. Let me clarify.

I don't think that having or not having a gallbladder is problematic, one will absorb and excreet the same amount with or without it. Timing does change though. My point is that this toxic bile (and I'm not talking about the normal toxicity of bile) is more toxic due to a reaction with NSAIDs. At least according to the review.

Indeed it is vital, the point about excess bile was that the body is capable of measuring whether there is not enough or too much and (so long as things are not busted) can regulate this. But it does not regulate the toxicity of the bile, it doesn't nessearily measure bile for it's toxicity and then pruge it if it's to toxic. There isnt' a mechanism in place for that as far as I can tell. Though if enough damage were done to the ileum by this toxic bile then indeed it we be eliminated via the stool unless the bacteria were able to convert it for reuse in the colon.

Actually the body is very good at recycling bile, it's expensive to make for the body, the same material is used for creation of steroids and many other chemicals in the body. Vitamin D, Cortisol, Testosterone, Estrogen, Progesterone, Cholesterol, etc. I want to say it's somewhere around 80% is recycled, but I'd have to dig out the studies to say for sure.

Mike

[mle_ii]

Ha, it's even better at recycling than I thought. 95% according to this article:
http://www.wjgnet.com/1007-9327/12/7710.asp
Analysis of ileal sodium/bile acid cotransporter and related nuclear receptor genes in a family with multiple cases of idiopathic bile acid malabsorption

The enterohepatic cycling of bile acids is an extremely efficient process, and less than 5% of the intestinal bile acids escape reabsorption and are eliminated in the feces.

[cludwig]

Hi Friends,

Just food for thought....but that is exactly how I felt the last very long 15 months...like my body was dealing with something very toxic. At my best I was feeling just crummy...but four or five times a day I just felt like something was swarming my body...was like walking into a wall...had to lie down and breath through it...10 minutes to 45 minutes. I am now assuming it was toxic bile since I can very happily say it isn't happening since the gallbladder is gone. My BMs are going in the norman direction as well.

The scary part of all this is that I had an abdominal CT scan at the Mayo in dec. and an endoscopic ultrasound 10 days before my gallbladder was removed and both said it was perfect. So, what the heck is that about???? The "autopsy" said it was inflamed, rubbery,thickened with much scar tissue from years (actually decades) of disease....but no stones. So am I just an unusual case or are our doctors simply not very good at diagnosing this problem.

I am trying to find out just how many lymphocytes I had in my first biopsy to see for myself if my LC dx is correct or not....and how exactly do they draw this line in the sand that says this is LC and this isn't. The symptoms that I experienced were so similar to you alls...the dx food allergies,gurgling , bloating, D, brain fog. It all leads me to wonder about the people who only get partial relief from entocort and diet...that something like this could be the root.

It is just hard to know what to do about it since they won't consider it unless you have stones...frustrating.

Love,
Cristi

[Reggie]

This is especially fascinating to me since I just started on Cholestyramine (CH) resin last week. As I learned from searching here, it binds with bile and causes it to be purged so new bile has to be made in the liver. It was designed to be a cholesterol reducer, because the liver uses cholesterol to create the new bile, lowering what you have left. If I got it right.

I'd been on bismuth for a month before I started this, and my D was decreasing - one day on, 3 days off, erratic. Since I started on CH, the only D I've had was after the day I only took half my 4 doses, and both those doses were in the middle of a meal instead of just before.

My doctor didn't tell me to take it just before a meal. I figured that out from reading the thread here about Caltrate 600, and how that had to be taken just before the first bite of a meal so it could interact with bile.

I may have this all scrambled, brain fog is my excuse. But in case you guys think you're just having some kind of intellectual discourse, you should know it's giving me a lot of hope that I finally have control.

So what happens with Cholestyramine? Do I take it forever? Once my bile is cleaned up, am I good to go until it's fouled again? I didn't take all that many NSAIDs before LC, but I tried advil 6 times a day for 3 days during my remission last year and it gave my intense nausea and some D for about 10 days after. I'll never do that again.

[tex]

Cristi,

I believe the problem with your gallbladder issue is the fact that doctors don't have to think nearly as much, as they used to have to do. These days they rely on sophisticated tests, and let the machines do their thinking for them. This works most of the time, but it causes them to miss some very obvious diagnoses, that they wouldn't be missing, if they just used a little common sense. I'm not a doctor, but to me, it was pretty dang obvious that, regardless of what their tests were showing, you had a gallbladder problem. As I pointed out in my initial post about it, you had the classic symptoms of gallbladder disease. The doctors couldn't see that, though, because they let their machines do their thinking for them. An old fashioned country doctor, who had to work without all the modern equipment available today, would have recognized your symptoms immediately.

Doctors have become sorta like the weather forcasters we have these days. The more sophisticated their meteorological equipment becomes, and the more they rely on complex computer "models", to forecast the weather, the more unreliable their forecasts become. They've forgotten how to look out the window.

For roughly a month, beginning about the middle of January, our local temperature forecasts consistently overestimated the daily highs and lows, by at least four or five degrees, almost ever day and night. All they would have had to do, was to use a little common sense, and they could have done a much better job of forecasting the temps. Instead, they continued to rely on their flawed models, for their forecasts, instead of "looking out the window".

If I recall correctly, the threshold for a diagnosis of LC, is roughly 20% lymphocytic infiltration. IOW, if roughly 20% or more, of the spaces between epithelial cells in the colon, contain lymphocytes, then LC is the "indicated" diagnosis.

The problem with this, as I've mentioned before, is that virtually all CC patients have some degree of lympocytic infiltration, and I really believe that virtually all LC patients have some degree of thickening of the collagen bands in their colonic mucosa. This isn't discovered in many cases, because of the hit and miss method in which biopsy samples are ususally taken. IOW, most GI docs don't know how to target the optimum locations for the collection of biopsy samples, simply because they don't realize that they can "see" the areas of inflammation in the colon, if they just learn how to look for them. Consequently, I suspect that most biopsy samples are probably taken in areas of light to moderate inflammation, and the more severely inflamed areas are overlooked, in many cases.

What I am suggesting, is that I don't believe that there is any significant distinction between LC and CC. The different diagnoses are simply due to biopsy samples being taken at less than optimum locations. I believe that Dr. Fine shares this opinion, also.

I agree with you. Gluten sensitivity adversely affects many parts of the body, and it's easy to overlook some of the contributing factors, in the really severe cases. MC is not a "well behaved" disease. It tends to blur the boundaries, and confuse the issues, and confound the tests. It's in a league of it's own.

I'm glad you're feeling so much better, now.

Love,
Tex

[tex]

Hi Reggie,

Yes, I believe you have it right, and it's obvious that you're on the ball, since you figured out that the med needs to be taken at the start of a meal, not later, even though your doctor apparently overlooked that little detail. That information may not be in the text books, since this is almost surely an off-label use for Cholestyramine.

I'm glad that our ramblings have been of some help. I know that I've learned more here than I ever dreamed was possible, and I know for sure that I never would have been exposed to probably 99% of the information that I have learned here, if it were not for the free exchange of ideas and information that we enjoy here.

Cholestyramine is often used to treat diarrhea caused by gallbladder removal, or the removal of the ileum, (the lower third of the small intestine) - the theory being that in these circumstances, bile reaches the colon unimpeded, and acts like a laxative, thus causing diarrhea. As you pointed out, Cholestyramine absorbs and binds these bile salts, helping to improve the diarrhea problem.

With that in mind, I'm wondering if maybe you might just have a malabsorption problem in your small intestine, and once that problem is resolved, you might be able to stop using the Cholestyramine. If the malabsorption is due to gluten damage, then it should heal on it's own, provided you stick to a GF diet. If it's caused by dysbiosis, or SIBO, (Small Intestine Bacterial Overgrowth), then a probiotic, or a one-two punch with an antibiotic, followed by an appropriate probiotic, might be in order.

IOW, it could be that your problem might not be toxic bile salts, so much as unmodulated bile flowing into the colon. I'm just thinking out loud here, so please don't assume that any of this is chiseled in stone. Of course, one of the primary side effects of Cholestyramine is constipation, and it could be that this is the reason why your doctor prescribed it. Doctors often exploit such side effects, for off-label uses of certain meds.

Tex

[Reggie]

So many questions, so few answers. Thanks for your reply, Tex. I'm actually taking VSL#3 now. I couldn't face doing an antibiotic first, though.

While I've never had gall bladder problems, I did let my GERD go until I could barely swallow. My esophagus eroded, and the tissue was replaced with intestinal tissue (Barrett's Esophagus). I've been on pantaprozole for about 3 years and I'm doing well. I don't know how bile enters the stomach, but I do wonder if my acid problems could have damaged that entrance point. Who knows, maybe my bile just roars right in.

My elmination diet experiment didn't show any gluten problems. I was off it for 3-4 weeks and felt no different. I had no response to adding it back in. I'm pretty suspicious of corn, however. The whole thing felt like a total failure because I panicked when D returned before I added anything at all back in. I'm going to do Dr Fine's stool tests instead as soon as I get off the bismuth - probably this week.

[Polly]

Hi Reggie,

So glad to hear that things are improving.

I may be repeating myself here, but are you aware that the proton pump inhibitor group of drugs can actually cause MC? This group includes Prilosec, Prevacid, and yes, Protonix (pantaprozole). We have had at least 2 members in the past who believed their MC was caused by these drugs - interestingly enough, I believe the MC resolved when the drug was withdrawn. Of course, neither is still posting here, so I don't know if the remission was longterm or not. You may want to ask your doc if there is a drug other than a proton pump inhibitor drug that would be effective for your GERD.

Tex, I agree that the diagnosis of the type of MC may be dependent upon the quality, location and number of the biopsies. Both LC and CC have lymphocytes. The collagen is the key - if collagen and lymphocytes are seen together, it is called CC; if no collagen is seen (only lymphocytes) then it is called LC. In my original colonoscopy, 8 biopsies were taken - throughout the length of the colon. Not one of the biopsy specimens contained any collagen......thus I was diagnosed with LC. I know in the past some researchers believed that CC was a more advanced stage of LC. I don't believe I've heard Dr. Fine say that one form can turn into the other......what I have heard him say many times is that, with regard to how they are TREATED, LC and CC are the same. The same treatment applies to both, IOW.

Love,

Polly

[tex]

Hi Polly,

Okay, I realize that I'm quibbling over semantics, here. LOL. From Dr. Fine's website:

What is the difference between the terms microscopic colitis, collagenous colitis, and lymphocytic colitis?

These are three terms used to describe essentially the same syndrome. Microscopic colitis is the most general term and the one I prefer. Collagenous colitis is used when collagen (a pink protein seen on a biopsy of the colon) is present, and some people use the term lymphocytic colitis when there is no excess collagen because there are lymphocytes seen in the tissue. However, lymphocytes are seen in collagenous colitis as well, making lymphocytic colitis an inaccurate term. There is no evidence that these different forms result from a different cause, I have recently found that the causative genes are the same, they are both associated with gluten sensitivity (see below), and they both respond equally to treatment.

IOW, it's the same disease, but some patients just don't present with collagen deposits, just as in many other diseases, where all patients don't present with all known symptoms.

I have to get back to work, so I'll have to try to relocate the atticle/s where the segueing of LC into CC and vice versa is discussed, when I have more time. It wasn't from Dr. Fine's site.

Love,
Tex

[Polly]

Exactly, Tex.

We are saying the same thing......that the 2 different "forms" (Dr. Fine's term) of the disease as diagnosed by biopsy (LC and CC) are probably caused by the same disease process and are therefore treated the same. According to what you highlighted in red, I would imagine that Dr. Fine would prefer the biopsy designations to be CC and non-CC, rather than CC and LC. That would highlight the presence or absence of collagen more appropriately.

Obviously, both LC and CC have associated gluten sensitivity and both are treated the same. However, there still may be some minor differences. I recall that when members on Sally's old board first started going GF, it seemed that the LC folks responded more quickly to diet than the CC folks. That might lend credence to the theory that CC (with the deposit of collagen) is a disease of longer standing, of more chronicity than LC.

Love,

Polly

[mle_ii]

Couple of comments.

I see what Dr Fine is saying as well. He's not really saying that they're the same disease but, as Polly mentioned, that calling one LC and one CC seems odd in that CC also has the same symptoms of increased lymphocytes as LC does. So as Polly said it'd be more clear if one said CC and non-CC or even something like LC and CC+LC.

But then to me it's all just silliness. I've mentioned before that I see CC and LC as symptoms of something else and not diseases per se. I see it as it's like saying that I have the disease of a runny nose. Heck we even treat it in similar ways, how do we get rid of a runny nose by blocking production of mucus using an anti-histamine. So to stop LC/CC we block diarrhea by giving someone an anti-diarrheal. Makes perfect sense doesn't it? But we all know that blocking a symptom does not cure a disease. In fact I'm guessing that this same inflammation that looks like LC/CC occurs in other diseases, just like a runny nose also appears in other diseases, colds, allergies. So let’s say our runny nose is a function of a cold, well, how helpful is it to treat it like an allergy? Not very. Just like treating LC/CC like most docs do isn't helpful.

So what we really need to do is to find the problem, figure out what caused it and fix that.

My guess would be that once we find the real cause then we don't need all these meds (like tex said about Cholestyramine), or cortisol, or anti-diarrheal, etc. I would also say that most food allergies/sensitivities will go away, notice I said most but not all. Some foods I see as poisons no matter how you look at them.

[mle_ii]

So many questions, so few answers. Thanks for your reply, Tex. I'm actually taking VSL#3 now. I couldn't face doing an antibiotic first, though.

Awesome, so how has the VSL#3 been for you so far? Oh and in a way you are taking an antibiotic, both via the probiotic and also via the peptobismol.

While I've never had gall bladder problems, I did let my GERD go until I could barely swallow. My esophagus eroded, and the tissue was replaced with intestinal tissue (Barrett's Esophagus). I've been on pantaprozole for about 3 years and I'm doing well. I don't know how bile enters the stomach, but I do wonder if my acid problems could have damaged that entrance point. Who knows, maybe my bile just roars right in.

How do you know that bile was getting into your stomach? It's possible, I'm just curious. Some of the ways it does get in is by slow gut motility (of either the large or small bowels, but most likely the small), bacterial overgrowth, allergic reactions, damage done to or problems with the sphincter between the stomach and small intestine, hormonal/chemical imbalance. Which could even be caused by the very proton pump inhibitors that folks are perscribed.

I'm curious did you get your stomach acid levels tested before they gave you the proton pump inhibitor? What tests have they done and what have they found thus far?

My elmination diet experiment didn't show any gluten problems. I was off it for 3-4 weeks and felt no different. I had no response to adding it back in. I'm pretty suspicious of corn, however. The whole thing felt like a total failure because I panicked when D returned before I added anything at all back in. I'm going to do Dr Fine's stool tests instead as soon as I get off the bismuth - probably this week.

I hated the elimination diets and now I see why they're so hard to figure out. Did you try eliminating everthing all at once except for the extreem basics? One of the problems with elimination diets is that one food can hide the problems of another. So let's say that corn and gluten are your problems. You eliminate gluten, don't get better and assume that gluten isn't the problem, add it back in, try corn and don't get better, so you throw your arms up and give up. Instead removing both gluten and corn, you got better. Added corn back in and saw symtoms. Took it out. Added gluten saw symptoms. Took it out. I really wish it wasn't so difficult to figure out.

[tex]

Polly,

The treatment response rate differences between patients diagnosed with "LC" and "CC", respectively, may indeed be a statistically measurable phenomenon, that is directly related to Paneth cell metaplasia, as per this quote:

In patients with collagenous colitis, Paneth cell metaplasia was associated with more severe disease characterized by the presence of abdominal pain (P<0.001) and a higher frequency of bowel movements (more than three bowel movements/day; P=0.06).

from this College of American Pathology article:

http://www.cap.org/apps/docs/cap_today/ ... 01_03.html

Note that in this study, 44 percent of CC patients, but only 14 percent of LC patients, had Paneth cell metaplasia. I think that this is an important factor in the treatment of MC, that has been largely overlooked. I'm not implying that it means that the treatment should be changed, I'm just suggesting that this may explain why some cases are much more difficult, and take longer to resolve.

As you are probably aware, the term "Paneth cell metaplasia" has rather unpleasant implications, but I'm not at all sure that this implies any increased risk to patients with MC.

http://www.ncbi.nlm.nih.gov/entrez/quer ... t=Abstract

http://www.carcinogenesis.com/content/4/1/5

Love,
Tex