Update on my "smoldering fire"

[Tor]

I was diagnosed with collagenous colitis 3 years ago, and joined this group shortly after. I haven’t been posting much lately, but I’ve been lurking. There are some really knowledgeable people here!

I’ve been making a lot of progress in the 3 years since I was diagnosed, and some new problems have risen. Some of this might be interesting for more than me, and some of you might have some input to my current issues. Anyway, I’m sorry for the detailed and lengthy story.

My diarrhea started almost 25 years ago and was a constant companion every day until my diagnosis. 3 years after the D. started I was diagnosed with a slow developing kind of diabetes 1. 8 years after that I was diagnosed with vitiligo. That makes collagenous colitis my 3rd autoimmune condition. What all of them has in common are slow development and a sort of low grade inflammation.

In 2010 I was very weary of the D., and some new symptoms had emerged; fatigue, myalgia, arthralgia in the small joints of my feet and acne/papules. My sister has celiac disease and during the assessment leading up to the colitis diagnosis I went through gastroscopy for the 2nd time. Gastroscopy concluded with “unspecific gastroduodenitis” and celiac antibodies was negative. I also had a SeHCat exam done, and that showed low reuptake of bile acids, but slightly above the diagnostic limit for bile acid malabsorption. A Dexa-scan revealed osteopenia and my iron-level (Hb) had been low for the last 4 years.

I took tests for IgA against casein and gliadin at a private laboratory. IgA against gliadin was more than 6 times the normal limit. As Tex will know, the gastroduodenitis and the raised IgA against gliadin are very consistent with Kenneth Fines and Ritva Koskelas research on Microscopic colitis. The private laboratory also performed a lactulose/mannitol-test that showed borderline leaky gut (1.49 < 1.50). I’ve also had ha gene test done by 23andMe. Some of the more interesting finds from that was rs2187668(A;A), rs1800629(A;A), homzygous deletion of C4A, rs2670660(G;G), rs6502867(C;T) and rs3184504(C;T). These few alone accounts for hundreds, if not thousands, of research articles on autoimmunity.

Rs2187668 (HLA-DRB1*0301/HLA-DQ 2.5), rs1800629 (TNF α, TNF-308.2) and deletion of C4A are linked, and probably the most autoimmune risk alleles identified to date with high risk for celiac disease, collagenous colitis, diabetes 1, lupus, autoimmune hepatitis and several others. When vitiligo appears together with other autoimmune conditions these genes are frequently found in vitiligo too. The combination of rs2670660 and rs6502867 (GCT) confer risk of vitiligo and most of the other autoimmune conditions noted above. Rs3184504 is identified as a risk allele for diabetes 1, celiac disease and has genome wide impact for autoimmune hepatitis.

Two different research projects published in well-known serials have found the risk for celiac disease in rs2187668(AA) positive siblings of celiacs to be 24 % and 28 %. If one adds the IgA-antibodies, iron deficiency, osteopenia and leaky gut, I guess I tick almost every box for gluten sensitivity. As a result of this I now get the same cost refund for gluten free food from the Norwegian government as celiacs do. The Norwegian government has also granted me a compensation (almost $50.000) for seventeen years belated diagnoses of collagenous colitis. Biopsies were taken for the first time on the sixth! colonoscopy.

But the road to full recovery has been long and winding. At first gluten free diet did nothing for me, probably due to multiple food sensitivities and an extreme sensitivity for coffee. At first I needed 9 mg of Entocort to keep the D. at bay, then 16 mg of cholestyramine, then 4 mg of cholestyramine and for the last few months I’ve been in total remission without any medication. The only things I react to now are gluten, coffee, tea, aspartame and strong spices. The other sensitivities seem to have waned. The reaction to gluten is slow; I don’t react to small amounts over a short period of time. And that’s just why this has taken me so long to figure out.

But alas there are more pieces to this puzzle. The fatigue, myalgia, arthralgia and acne didn’t wane with the inflammation in the gut, and in the spring of 2015 symptoms of peripheral neuropathy and vasoconstriction in the feet debuted. Towards the end of 2015 I decided that there probably was another autoimmune condition as well. My guess was that this condition debuted with the fatigue, myalgia, arthralgia and acne in 2009/2010. Because of the genetics and the symptoms I saw a rheumatologist last February with the suspicion that it might be a mild form of lupus (subacute cutaneous lupus) with secondary Raynaud’s phenomenon, but all serology was negative and the rheumatologist found no damage in the joints in the feet. She suspected that the symptoms were secondary to the colitis and diabetes.

But one of the blood test results caught my eye. Anti smooth muscle antibodies was measured to 1:80 which is somewhat suspicious of autoimmune hepatitis. Anti F-action was close to the cut off (18 <20). The most prevalent symptoms of autoimmune hepatitis are fatigue, myalgia, arthralgia and acne. Because of the symptom overlap between autoimmune hepatitis and lupus, autoimmune hepatitis used to be called lupoid hepatitis.

On my next visit to my gastroenterologist I asked him to repeat the liver tests. He agreed, and this time the Anti Smooth muscle antibodies came back at 1:40 (just positive), but the anti F actin was by accident analyzed by two different laboratories; one came back with 22 (<20) and the other 41 (<20). This is an ELISA test, so the discrepancy is strange. Anti F actin of 41 is extremely specific for liver inflammation, for the most part due to autoimmune hepatitis. Liver enzymes and other liver tests were still completely normal, and the gastroenterologist and a hepatologist colleague didn’t want to take a liver biopsy, but I insisted. I found the anti F actin to be more specific than the liver enzymes is sensitive.

My gastroenterologist tends to listen to his patients, and I got my way. To his surprise, the biopsy showed what they after sending it to another hospital for a second opinion called “Light portal fibrosis and focal loss of parenchyma with necrosis and lymphohistiocytic infiltrates”. There was no interface hepatitis, which is a hallmark of autoimmune hepatitis. The pathologists concluded that the changes where unspecific, but could be due to circulation disturbances or drugs. My gastroenterologist gave me the diagnosis “smoldering fire” for the whole situation, which I found very poignant.

The only liver toxic drug I’ve been taking is statins, but I’ve been a quite heavy user of aspartame as well. In a new article in the Lancet statins was estimated to cause liver injury in only 1 per 100.000 patients. Aspartame is supposed to be safe in 3 times the quantity I’ve been using. What’s way more prevalent is liver damage due to gluten. Approximately 40 % of celiac patients have raised liver enzymes at the time of diagnosis, including my sister. From what I gather the liver injury heals in most celiacs, but with long exposure to gluten the hepatitis can become chronic - or autoimmune. Well, in my case the exposure time has been long, and I have an undisputed talent for autoimmunity.

When my biopsy was taken, I started a new 3 month cycle of Entocort with the gut seemingly in remission. Within two weeks of 9 mg Entocort the fatigue, arthralgia and myalgia was gone. While tapering the Entocort, the arthralgia and myalgia slowly came back. The neuropathy might have been a bit better, but it was inconclusive. The fatigue is still gone now after two months off Entocort.

In December I saw a cardiologist and a neurologist regarding the vasoconstriction/neuropathy. A thermal test was done. The results were within normal limits, but they seem to have concluded that I have peripheral small fiber neuropathy. Both the cardiologist and the neurologist were very vague on the etiology. The neurologist said that newer research has shown that there are other factors than glucose levels involved in diabetic neuropathy, and that neuropathy correlates with multiple autoimmune conditions, not only diabetes. The cardiologist speculated that my symptoms could be due to immune complexes irritating the nerves in the blood vessels. I find that this correlates with C4A deficiency causing reduced ability to clear immune complexes. My blood glucose levels have been low for all my 20 years with diabetes and currently its just within the normal levels for healthy people.

I’m also heterozygote (rs4149056(C;T), rs4363657(C;T)) for a gene that causes statins to build up in the blood instead of being fully metabolized in the liver. My total cholesterol level has at times been as low as 3 mm/l (116 mg/dL). As Tex previously has pointed out, the myelin cover over the nerves are made of cholesterol.

I’m taking multivitamins, omega 3, high dose magnesium (Doctor’s Best), high dose vitamin D (Doctor’s Best), vitamin K2 (Doctor’s Best) and calcium. I bathe in Epsom salt once a week. I’ve been taking B12 injections every 3rd month for over a year. I’ve been on 40 mg of Simvastatin between 2008 and 2013. For the last 3 years I’ve been off and on statins and have been taking only 10 mg of Pravastatin for the last couple of years. From the start of January I’ve quit statins and aspartame completely, and cut my alcohol consumption in half to about 7 units a week. I’ve been completely gluten free for eighteen months. My idea is that if the anti F actin doesn’t wane with all possible offenders gone, I can conclude that the hepatitis has become some kind of low grade (microscopic?) autoimmune hepatitis, probably due to long time gluten exposure, leaky gut and genetic predisposition.

I hope someone can get something out of this extremely long and winding story, and maybe give some input regarding the unsolved and unspecific issues. Maybe Tex?

Regards,
Tor

[Gabes-Apg]

Tor
thanks for sharing

I had similar type situations where i had moderate to severe renal impairment for 18 months (of unknown cause)
my thought is - the combo of years of nutritional deficiencies, leaky gut and build up of toxins, heavy metals, inflammation caused stress to other organs.
in my case I think MC is symptom of these issues - not root cause condition.

came across this article today - and thought you might be interested

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901442/
Common variable immunodeficiency (CVID) is a common primary immunodeficiency characterized by a failure in B-cell differentiation with defective immunoglobulin production. Affected patients are uniquely susceptible to recurrent infection with encapsulated organisms and have an increased propensity for the development of inflammatory and autoimmune manifestations. The diagnosis of CVID is commonly delayed and the underlying cause of the disorder is not understood. Replacement antibody therapy reduces the risk of serious infections. However, optimal treatment regimens for the uncommon manifestations associated with this disease, such as granulomatous lymphocytic interstitial lung disease, require further research.

[tex]

Hello Tor,

That's a very interesting history. You're correct that there are some very knowledgeable people here — you are definitely one of them. You've done a lot of investigative research.

Here are a few random observations that came to mind as I read your post:

Diabetes, vitiligo, and MC have something else in common other than slow development and low level inflammation — they are all symptoms of magnesium deficiency. But that's not surprising because magnesium deficiency has been shown to slowly cause the development of diabetes and a deficiency also promotes low level inflammation (I can cite references if you need them).

And there is an association between magnesium deficiency and iron deficiency. That is to say, people who are magnesium deficient are more likely to be iron-deficient. Both magnesium deficiency and iron deficiency compound the fatigue associated with MC.

But alas there are more pieces to this puzzle. The fatigue, myalgia, arthralgia and acne didn’t wane with the inflammation in the gut, and in the spring of 2015 symptoms of peripheral neuropathy and vasoconstriction in the feet debuted.

My peripheral neuropathy and vasoconstriction in the feet also showed up later.

but all serology was negative and the rheumatologist found no damage in the joints in the feet. She suspected that the symptoms were secondary to the colitis and diabetes.

In my case at least, I'm convinced that it was due to a combination of nerve damage due to many years of untreated gluten sensitivity, and my intensifying chronic magnesium deficiency intensified the symptoms.

Aspartame is supposed to be safe in 3 times the quantity I’ve been using.

Virtually all tolerance levels are determined for so-called "normal" people, so they may or may not apply to people who have compromised digestive or immune systems. Most of us here cannot tolerate aspartame.

Both the cardiologist and the neurologist were very vague on the etiology. The neurologist said that newer research has shown that there are other factors than glucose levels involved in diabetic neuropathy, and that neuropathy correlates with multiple autoimmune conditions, not only diabetes. The cardiologist speculated that my symptoms could be due to immune complexes irritating the nerves in the blood vessels. I find that this correlates with C4A deficiency causing reduced ability to clear immune complexes.

I was even diagnosed with Parkinson's disease in 2009 because all my reflexes below my knees were almost none-existent and I had balance issues and gait issues. But despite the fact that the neurologists who examined me could not find a cause for my symptoms, none of them were willing to admit that the symptoms could be caused by nerve damage due to years of untreated gluten sensitivity. I also have methylation issues due to MTHFR gene mutations, and I've been taking Metanx (a prescription blend of the active forms of vitamins B-6, B-9, and B-12) since the date of that diagnosis. It has not resolved all of the symptoms, but it has helped (especially my reflexes). Less than a year later, a different neurologist agreed with me that I probably do not have Parkinson's disease, but she still could not point to a cause for my symptoms, and she also refused to acknowledge that the symptoms could be associated with damage caused by untreated gluten sensitivity. Back then (2010) I didn't realize that I had a chronic magnesium deficiency.

I note that you're taking a calcium supplement. Are you aware that calcium (in the presence of adequate vitamin D) displaces/consumes an amount of magnesium approximately equal to the amount of the calcium supplement? IOW, if we take a calcium supplement we need to boost our magnesium intake by approximately an equivalent amount. That said, you may be getting more than enough magnesium despite that extra demand, so I'm not suggesting that you need to increase your magnesium intake — I'm just pointing out that relationship in case anyone reading this is in a similar situation.

All in all, IMO there are so many complex issues involved with these syndromes that medical science is only able to scratch the surface with the current level of understanding based on available research data. Every case is unique and that makes medical intervention extremely difficult because physicians are trained to view diseases as isolated issues (not interdependent) so that they can be treated with a one-size-fits-all approach. But as we learn by experience, AI issues especially tend to affect (or promote) other AI issues because they probably have a common etiology that can be traced back to years (or decades) of chronic nutritional issues (such as vitamin D and magnesium deficiencies). And much of the neurological damage that these deficiencies cause is not reversible (at least not completely).

But of course, that's mostly speculation at this point.

Thank you for sharing all that insight.

Tex

[Gabes-Apg]

Further to Tex's reply and my reply

I have not had any kidney/renal issues since resolving my Magnesium deficiency and resolving other nutritional deficiencies.

[Tor]

Thanks, Gabes and Tex

I read the CVID-article with interest, but I don't think CVID applies to me. The autoimmunity bit is very much present, and so is the hepatitis. But IgG and gamma globulin levels are normal. I'm not prone to infections and viruses, in fact the opposite. Except for a few short-lived episodes of stomach flu, I've not been bothered with viruses or infections in over 30 years. I recently read an article which addressed the relatively high prevalence of the 8.1 ancestral haplotype despite its predisposition for autoimmunity. More than 25 % are heterozygote for DQ2.5 in Northern Europe. They concluded that there must be a protective element as well.

I see now that I was not accurate in my previous post when it comes to my magnesium supplementation, its way lower than I thought. I discovered Doctor's Best through this site in May last year, and have been taking 2 tablets of chelated magnesium each day since. I see now that the recommended daily dose is 4 tablets. In addition there is some magnesium in my multivitamin, but only 27 % of the daily recommendation. In addition I've been taking weekly baths with Epson salt. My magnesium supplementation is way lower than my calcium supplementation which is prescribed by my gastro doc at 500 mg. I doubled the vitamin D dose to almost 10.000 units after reading the extremely interesting articles Tex referenced about vitamin D and leaky gut/Crohns.

I will go off the calcium supplementation when my current box is empty. My absorption should be way better now, and I'm not on Entocort. I will also try to adjust the magnesium dose. What amount of magnesium do you take, Tex? I'll be glad if you could post the references to the magnesium articles, Tex. That might be an interesting read. My gastro doc agreed that magnesium deficiency was an underdiagnosed issue, by the way. No protests there.

I'm also glad that you point out the relationship between gluten exposure and peripheral neuropathy, Tex. I've read the articles by Hadjivassiliou (University of Sheffield), and I think they're good. There have been some dispute, though, but Sheffield seems to have beaten Nottingham. Actually the neuropathy debuted towards the end of a 6 week gluten provocation before taking the IgA and leaky gut tests. At the time I thought gluten was the offender, but 18 months of gluten free diet has not prevented it from getting slightly worse.

What I set out to do over a year ago was to exclude gluten, rheumatic illness, thyroid illness, vitamin B deficiency and statins/cholestyramine, and then I became aware of the magnesium issue in the spring. As Tex writes, nerve damage isn't always reversible, and the same applies for liver damage. I guess I still can't rule out gluten, magnesium deficiency and/or too low lipids when it comes to the neuropathy.

Thanks again for the quality control, Tex and Gabes!

Tor
BTW: Is there a way to make tables on this board? I tried using html and BBCode, but neither effort succeeded.

[tex]

Tor,

Actually I take 200 mg of magnesium citrate after breakfast, and 200 mg of magnesium glycinate after each of the two following meals, for a total of 600 mg of magnesium. The reason I take magnesium citrate following breakfast is because I have an ileostomy. With an ileostomy, constipation can be more than just an inconvenience, so the magnesium citrate is just insurance to make sure that nothing in my stool has agglutinated (clumped together) during the night. At 200 mg, that's not enough magnesium citrate to act as a laxative, but it's enough to keep an ileostomy working smoothly. If I didn't have an ileostomy, the magnesium I take would all be magnesium glycinate, because it's the form of magnesium that's the least likely to have a laxative effect.

Because of the colectomy/ileostomy, plus the removal of part of my terminal ileum, I'm subject to short bowel syndrome issues, so I take a multivitamin. FWIW, my multivitamin also includes 80 mg of magnesium, but like most multivitamins, it's in the form of cheap magnesium oxide. I completely ignore that source of magnesium because we can only absorb about 2 % of the magnesium in magnesium oxide. It doesn't take very much unabsorbed magnesium oxide to make a good laxative because when it mixes with the water in the digestive tract it forms magnesium hydroxide, also known as milk of magnesia.

I'll be glad if you could post the references to the magnesium articles, Tex. That might be an interesting read. My gastro doc agreed that magnesium deficiency was an underdiagnosed issue, by the way. No protests there.

Kudos to your gastro doc. I noticed several years ago that both clinicians/physicians and medical researchers in the Scandinavian countries seem to be way ahead of U. S. GI specialists in their understanding of digestive system problems.

OK, this first reference is about the association between magnesium and C-reactive protein levels. It's from pages 20–21 of the book Pancreatic Cancer - A Guidebook for Prevention.

But why does taking a magnesium supplement reduce the risk of developing pancreatic cancer?
For one thing, magnesium is a vital electrolyte. So when it becomes deficient, some of the many normal body processes that depend on it may not be able to proceed normally, and this can have adverse consequences if it occurs on a regular basis. For example, a magnesium deficiency obviously has a potent effect on the pancreas because (again, as we shall see in the next chapter) it causes the pancreas to produce less insulin. Magnesium is also known to have anti-inflammatory properties.

This observation is pure speculation, but there is a very good chance that the reason why magnesium helps to prevent PC may be due to this anti-inflammatory characteristic. C-reactive protein is commonly used as a way to measure the level of inflammation in the body. Research shows that taking a magnesium supplement reduces C-reactive protein levels.

One study based on sample data from the National Health and Nutrition Examination Survey that covered the years 1999–2002 showed that among U. S. adults who were not taking a magnesium supplement, only 21.9 % met or exceeded the RDA for magnesium (King, Mainous, Geesey, Egan, & Rehman, 2006).18 These researchers concluded that people whose total daily magnesium intake was less than the RDA were approximately 40 % more likely to have an elevated C-reactive protein level.

And here is reference 18 from that quote:

18. King, D. E., Mainous III, A. G., Geesey, M. E., Egan, B. M., & Rehman, S. (2006). Magnesium supplement intake and C-reactive protein levels in adults. Nutrition Research 26(5), 193–196. Retrieved from http://www.nrjournal.com/article/S0271- ... tract?cc=y

And for the association of magnesium deficiency with insulin resistance and diabetes — from pages 25–26 of the same book (Pancreatic Cancer):

But this leads us to the magnesium connection again.
As mentioned in the previous chapter, magnesium deficiency plays an important role in the development of insulin resistance and type 2 diabetes. Researchers have shown that both hypertension and type 2 diabetes involve low intracellular magnesium levels (Takaya, Higashino, & Kobayashi, 2004).26 In the research article cited, Takaya, Higashino, and Kobayashi (2004) concluded that because magnesium is necessary for the proper utilization of glucose, and it's also used for insulin signaling, an intracellular magnesium deficiency may alter glucose availability and contribute to the development of insulin resistance.

Magnesium and insulin are co-dependent.
One cannot function properly without the other. And this is a 2-way street in many regards. Not only does a magnesium deficiency cause insulin resistance in the cells of the body, and reduced insulin production by the pancreas, but there is a reciprocal effect. Insulin is responsible for the transport of nutrients to locations where they can either be immediately utilized or stored for future use. When the availability and effectiveness of insulin is compromised, extra magnesium in the blood cannot be properly stored, so most of it may be wasted, instead (Sircus, 2009).27

This can dramatically increase the odds that diabetes patients may develop a magnesium deficiency. And of course as the magnesium deficiency becomes worse, insulin resistance may increase and insulin production by the pancreas may decline even further.

But even stronger evidence of the association between magnesium deficiency and diabetes has been found by researchers. Research published by Hruby et al. (2014) found that higher magnesium intake reduces the risk of insulin resistance and the risk of progression from a prediabetic condition to diabetes.28 In that study, people who had the highest magnesium intake had only about half the risk (53 %) of metabolic interference or diabetes development compared with those who had the lowest magnesium intake. This information is especially important for those who have been told by their physicians that their blood test results indicate that they are at a stage known as prediabetes.

And here are references 26–28

26. Takaya, J., Higashino, H., & Kobayashi, Y. (2004). Intracellular magnesium and insulin resistance. Magnesium Research, 17(2), 126-136. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15319146

27. Sircus, M. (2009, December 8). The Insulin Magnesium Story [Web log message]. Retrieved from http://drsircus.com/medicine/magnesium/ ... um-story-2

28. Hruby, A., Meigs, J. B., O’Donnell, C. J., Jacques, P. F., & McKeown, N. M. (2014). Higher Magnesium Intake Reduces Risk of Impaired Glucose and Insulin Metabolism and Progression From Prediabetes to Diabetes in Middle-Aged Americans. Diabetes Care, 37(2), 419-427. Retrieved from http://care.diabetesjournals.org/content/37/2/419

BTW: Is there a way to make tables on this board? I tried using html and BBCode, but neither effort succeeded.

There's no direct way to add a table, but if you can save the table as an image file (JPG file), an image file can be added anywhere in a post by using the "Add Image to Post" link, (the link is below the message composing window at the left hand end of the window). That link is not visible with the "Quick Reply" posting window in an existing thread, but if you click the "post reply" button, you will see the link below the "regular" reply window.

As always, you're very welcome.

Tex

[Tor]

Thanks, Tex!
I'll look into these articles with interest.

Tor

[Lilja]

Tor,

You may want try the liquid form of magnesium oil (chloride), which I have found way more efficient than even the glycinate tablets. I digest the liquid better than tablets. It's a bit costly to import and it's just within the limit of customs incl shipping to Norway. Dependent on the daily currency of USD to NOK, you should be able to stick below the limit of NOK 350.-, incl shipping costs.

https://www.rnareset.com/products/remag ... 3899661319

Lilja

[Tor]

Thanks, Lilja!

I'll look into the magnesium oil, but I seem to tolerate Doctor's Best chelated magnesium well. But that might change when I now have doubled the dose. But, so far, so good.

I know we have discussed the Norwegian governmental compensation for gluten free diet on an earlier occasion, Lilja. Did you notice in my original post that I got granted this compensation last year on the basis of NCGS?

I ran an ordinary provocation test, which was not blinded, and documented some gradual worsening of the D. over a 4 week period measured by the Bristol stool chart. I presented these results to my gastro doc with all the other circumstantial evidence (se my original post), and he recommended the diet compensation to the governmental agency.

You might want to try this as well. The key is supposed to be a provocation test in cooperation with a GI specialist, and a recommendation from the GI specialist.

Tor

[Lilja]

Thank you, Tor.

I have never heard of Norwegians with non celiac gluten sensitivity, who were able to obtain the compensation. But, as you mention I would have to go through a provocation test, which I would avoid at all costs. And, since grains have very little nutritional value, I might as well avoid grains totally.

Of course, one can ferment grains and bake one's own breads, but it's a lot of work just to obtain some diversity in the eating plan. I eat mostly well cooked meat, raw chicken liver, (with a lot of cinnamon), fish and herring, take coconut oil, several teaspoons with unrefined sea salt, buy Syrnet Mjølk (fermented low pasteurized, non homogenized milk) from Rørosmeieriet. I'm finally able to gain some weight. My tiredness is gone, and I can sleep through the whole night without the numerous trips to the bathroom. I think that all this is due to a diet with lots of nutrients.

I'm impressed that you did do the provocation test, and that you were granted the compensation

Lilja