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Leonard Weinstock, MD - Celiac Disease (2017 Conference) (LDN, low dose naltrexone)
Leonard Weinstock, MD - Celiac Disease (2017 Conference) (LDN, low dose naltrexone)
Celiac disease is a remarkable condition. It can present in so many different ways and have so many symptoms. What we're going to try is to hone down on the autoimmune conditions that are associated with it, which don't get as much attention in the literature as they should.
This slide goes over why we get celiac disease in the first place. Conceivably, it is through the food we eat, and that's actually what this slide shows. When we were hunters and gatherers millions of years ago, we did not grow our own wheat and make bread, pot pie and whatnot. We just ate fruits, nuts, and meat. And then the agricultural revolution came about. We were cultivating things. We were throwing new things at our body that we weren’t prepared for. That led towards development of antigens, and some people were not able to adapt to this.
The condition of celiac disease was noted by the Greeks. You can review this, but basically they said if they couldn't hold onto the food and the past food passed through them, basically diarrhea, they called those patients people “celiacs”. So celiac was identified by the Greeks years ago, but it wasn't until three different doctors in the 19th and 20th century really got a hold of things.
The common theme to the next 3 slides is that elimination diets work. Dr. Baillie described a diarrheal disorder with malnutrition and gas distention, but patients improved just going on a rice diet. Dr. Gee described it further and he too said not only that taking away gluten helped them, but reintroducing gluten led towards worsening of their disease.
And then Dr. Dicke in the Netherlands noted that wheat protein really was the trigger, that the wheat protein gluten gliadin was a true phenomenon that led towards his discovery, because basically there was no bread, no wheat in the Netherlands, and the patients got better and then they got quickly worse when bread was dropped from the skies by the Allies.
So that is the history of celiac disease. Celiac disease is remarkable because it's basically associated with so many other diseases itself. Some are autoimmune and some are not. So we’ll go quickly through the list of diseases it's associated with, and then try to hone in on autoimmune diseases, and then some of my own experiences as a clinician.
There are definite and possible connections. The definite ones are:
· dermatitis herpetiformis - I'm going to show you a case of that
· thyroid disease - Hashimoto's and Graves' conditions
· Inflammatory Bowel Disease (IBD) - though not autoimmune, is associated with it, a higher incidence of celiac in patients with Crohn's disease.
· celiac disease causes microscopic colitis, or collagenous colitis, which can get better with treatment
· hepatitis can be a factor
· Down syndrome is known to be associated with a higher incidence of celiac disease
· we're going into insulin dependent diabetes in a moment, but that's extremely common, both ways.
The prevalence of celiac disease in diabetes is a big factor. Up to 15% of children and 6% of adults who are diabetics have celiac disease. And vice versa, those who have diabetes for a prolonged period of time can get celiac disease in up to 5%.There's a shared genetic link that ties together a number of conditions as well. The next 2 slides show more conditions potentially associated with celiac disease, further links to celiac disease.
Here's a little bit about what it is, how common it is. Roughly 1%, a little less than 1% of people in Europe and USA have it. It's much more common in certain countries, such as Ireland. There's a specific genetic typing, an HLA type that is associated with it. So there is certainly within families, first degree relatives, 1 out of 22 will have it, roughly five times the normal population. Secondary relatives also show an increase. And if they’re symptomatic, in general, It's increased, so those patients who come to me with irritable bowel type symptoms, where there's shared symptoms, I'll screen for celiac disease. In adults it's more common, triple the rate in women, but in childhood it’s equal. It usually occurs at a young age, but we're seeing more and more of it. And in the 65 years and older group of patients, it's increased 5 fold.
It’s not exactly an allergy per se. We call it an immune regulated condition. And it really requires specific HLA genetic types to have it – DQ2 and DQ8. A problem is if you screen and test for these genes, you're going to find out that many have the genes, but don't have celiac disease. So it's a risk factor. And then there’s the reaction to gliadin and other proteins in the wheat plant; and in other plants, barley and rye. Specific lymphocytes are active and get active and stay active and make antibodies, resulting in damage or inflammation, which shortens the absorptive lining in the villi, and that leads to malabsorption.
There are known triggers: virus, different bacteria, and especially the enterovirus, that can trigger celiac disease. That's possibly because, at least in the virus, there's a similar look to the amino acid chains with gliadin. So you get enterovirus, the body that’s hyped up and ready to have a problem with wheat will get a whiff of this toxic gliadin and then start producing transglutaminase antibodies, which then sets off the disease. We often see disease <endoscopically> as little scallops, some flattening of different parts of the villi, and when the villi are long and thin as on the right you can absorb; but when they get blunted, you can’t absorb nutrients.
The classic presentation of diarrhea, fatty odor, fat in the stool and weight loss is getting less and less common: 50% present with extra intestinal or atypical symptoms. So many women are anemic because of it. They have trouble conceiving. Older people fall and have a fracture, and then they're discovered to have early onset bone loss because they're not absorbing vitamin D, and that results in major problems; and that may be their only symptom of celiac disease. A number of patients present with a skin lesion – we’ll show you what that looks like - dermatitis herpetiformis. And neurological problems: there are at least 9 different conditions ranging from migraines to ataxia imbalance, to Restless Leg Syndrome, that are part and parcel of celiac disease. As we go on, we'll talk about some of the factors that affect presentation.
I want to try to finish up this talk drawing examples and conclusions about how celiac disease triggers autoimmune diseases, and how these may need different specific treatments. The HLA turns out to be the histocompatibility locus association gene, is really one of the important links to get an auto immune condition. We do find this tissue transglutaminase, this protein antibody, in a number of different diseases, TG2 and TG3 in dermatitis herpetiformis, and TG6 in celiac ataxia. And that damages cells elsewhere in the body. There's an overlap with other antibodies, but it's not the classic ANA. It's mainly the celiac antibodies that are related to these other conditions.
The risk of autoimmune disease not only goes up in celiac disease with age, but also duration of their disease that's unrecognized. I think a lot of these patients who are older have unrecognized disease, or they have more and more exposure to the TG2 antibody for reaction-cross reaction to develop an autoimmune condition. By the time they're 20 years of age or more, 34% will have an autoimmune disorder.
Here are the classic autoimmune conditions that are associated with celiac disease. The range of diabetes, down at the bottom of the slide, varies quite a bit depending on which part of the country and study you're in, is between 2% and 16%.
In my own population, I looked at patients with celiac disease who saw me from January 2016 to December 2016, and found a number of patients with celiac disease who knew they had it, who were on a diet, and yet had additional symptoms. This slide shows what I saw in clinical practice: dermatitis, a painful macular rash, GI symptoms, a number of patients with upper abdominal pain with lymphocytic gastritis, a neuropathy patient with fibromyalgia syndrome, another neuropathy patient with peripheral neuropathy and restless leg syndrome; 5 patients with what we'd call irritable bowel syndrome, 1 with mast cell activation syndrome and POTS; and 2 with fibromyalgia.
Let's look at these patients a little more closely and look at the response to LDN. Here's case 1, a 37 year old who had Ehlers Danlos Syndrome who presented with bloating, a rash on the extensor surfaces of her knees and elbows and on the neck. She saw the allergist. She did not see us initially. The allergist did not recognize it as dermatitis herpetiformis and gave steroids, and ultimately stumbled on the idea of, well, maybe I should test for celiac disease. The panel was positive and he started her on a gluten-free diet. Patient’s bloating got better, and the rash improved to some degree, although there was this redness and discomfort on the elbows and knees, and the rash on the neck, which was itchy, continued. And here's the patient, showing this vesicular rash on the elbow; and we see some of the red scars close to the elbow, to the right. On the back of her neck, on the left, we see a persistent rash despite going on a gluten-free diet. I saw her after a year from the initial diagnosis. We tested her for bacterial overgrowth: that was negative. I started her on LDN, increased her from 1 mg every three days until she got up to 4.5 mg. After two weeks she had improvement in the neck and there was less redness on the knees and elbows. At 3 months all of her dermatitis, herpetiformis lesions resolved., I've kept her on LDN for prolonged period of time because of her Ehlers Danlos Syndrome, which helped her chronic pain. My thought was that reducing the total IgA produced by abnormal memory B-cells may have been the mechanism where LDN was effective.
When we talk about regulation of the B- and T-cells, we only have animal studies for this. On slide 28, we see a Dr. Zagon study, a companion piece for B-cell proliferation suppression by LDN, that is all we have at this point, unfortunately, to put our fingers on it and say, yes, LDN is very important on T- and B-cells
This slide is of a patient with celiac disease diagnosed for many, many years, on a very, very strict diet. Occasionally we'd have exposures, but generally not. For 5 years she had an autoimmune skin disease pop up to her feet, under her arms, a burning-itching sensation occurring literally half the month, lasting all day. Slide 30 shows the rash that she had. We gave her LDN and in the first month it dropped from 18 attacks to 6. In the second month it dropped down to 2 attacks, and each attack was less in duration. And that's all we did. She had other treatments by a dermatologist which had failed and she sought out treatment with LDN, and had a dramatic response of this autoimmune skin disease.
Of particular interest to me is Restless Leg Syndrome. It's a common disorder with a number of possible etiologies: certainly iron deficiency, we've looked at Small Intestinal Bacterial Overgrowth (SIBO), and inflammation. We're also going to talk about autoimmune conditions, which is a theory of why we're having a particular problem in the brain that leads towards endorphin deficiency. Celiac disease is something that I reported with others, to be associated with Restless Leg Syndrome. I looked at my own 85 patients, and during their lifetime, 35% had Restless Leg Syndrome while they were being seen by me; 25% had it versus 9% of their spouses, which is about the average for the prevalence in the population. About 21% had Restless Leg Syndrome before their GI symptoms. Iron deficiency played a role in this, and gluten-free diet syndrome played a role in them getting better, but not everybody got better. So the question is, did they have autoimmune antibodies that played a role?
One possible place for auto-antibodies to play a role is in the brain. Dr. Walters did an autopsy study of patients who had died with Restless Leg Syndrome, and found that 37% at a reduction in endorphins in their brain versus control autopsy subjects. So we see many more stains of MENK, methionine enkephalin, on the lower left, and fewer stains in the Restless Leg Syndrome subjects. So, what is destroying the cells that are producing the endorphin? Perhaps autoimmune antibodies or possibly T-cells, which are secreting chemicals directed against the cells.
This slide goes over my thoughts. Perhaps, however, this is a genetic problem. The cells that make the endorphins just die. Could it be T-cells? Could it be auto-antibodies? We don't know, but as far as therapy for LDN increasing the CNS endorphins, I think is very important because there are studies that show that endorphins improve iron deficient dopamine cells in the brain, and so that is important. Another thing to reflect on as far as CNS cells is where ataxia is a problem. In the cerebellum we see less cells there associated with celiac disease, and that's a place where a particular transglutaminase antibody was present. So there is rationale from a celiac induced ataxia that could apply to Restless Leg Syndrome. In my own practice this year, a patient with Restless Leg Syndrome and neuropathy took LDN at 3 mg and it improved both conditions.
Finally, we're going to wrap up with patients with celiac disease who present with diarrhea, despite sticking to a gluten-free diet. One potential complication of untreated celiac disease is Small Intestinal Bacterial Overgrowth (SIBO), because you're feeding the bacteria, and the treatment for that often works well is antibiotics. Leaky gut from chronic damage can play a role, and specific treatments for that can play roles, in terms of therapy to decrease the leaky gut. LDN may play a specific role there as well. And I have patients who claim that and endorse that. Some patients say they're on gluten-free diets and are not, and you can usually tell by just checking their antibody levels. There's an autoimmune disease of refractory celiac disease and ulcerative jejunitis. It is very difficult to treat, and often needs immunosuppression.
And then, microscopic disease. There are people who present with Irritable Bowel Syndrome (IBS). Let's look at these patients in my practice. Irritable Bowel Syndrome (IBS) was present in 5 of my patients who were in a remission state from celiac disease. They did not have bacterial overgrowth, but they developed persistent GI symptoms of abdominal pain with either M: alternating constipation and diarrhea, or D: diarrhea. Here are the 5 patients treated with LDN, a patient with mast cell activation syndrome and POTS who improved all three with LDN; a patient who went into remission for both IBS and fibromyalgia with LDN; improvement in two other patients with IBS; and then a fifth patient who could not tolerate LDN. It is exciting to be able to offer celiac patients a treatment for Irritable Bowel Syndrome, which is basically a lifetime curse. If you've got it, usually there's no cure, but these patients have dramatic improvement in many, and remission as well.
In summary, celiac disease is associated with many diseases, many of which are autoimmune, and can actually occur before or after the celiac diagnosis. In particular, thyroid disease, and perhaps Restless Leg Syndrome, can occur well before the celiac disease is diagnosed. The older you get, the worse the risk; and if you're a woman, the higher the risk of autoimmune disease. These diseases usually need specific treatment. It doesn't get better necessarily if you go on a gluten-free diet. Some studies say yes, some say no. However, LDN could be helpful for some of these patients, and it's something we need to keep our mind open to and share with others.
Keywords: low dose naltrexone, LDN, celiac disease, autoimmune, dermatitis herpetiformis, thyroid, Hashimoto's, Graves', Inflammatory Bowel Disease, IBD, Crohn's, diabetes, HLA, DQ2, DQ8, gliadin, gluten, diarrhea, Restless Leg Syndrome, TG2, TG3, TG6, fibromyalgia, neuropathy, ataxia, Ehlers Danlos Syndrome, gluten-free diet, B-cells, T-cells, Small Intestinal Bacterial Overgrowth, SIBO, MENK, methionine enkephalin, iron deficiency, leaky gut, Irritable Bowel Syndrome, IBS,