The Hows and Whys of Celiac Disease

Z. Myron Falchuk, M.D.
Gastroenterologist, Chief, Section of Gastroenterology Beth Israel Deaconess Medical Center,
Harvard Medical School Member, CSA Medical Advisory Board
Presentation to the 21st Annual CSA Conference, Warwick, Rhode Island
Lifeline, Spring 1999, Vol XVII, No 2, pp 1-4

 

I have been taking care of patients with celiac disease for many years. I arrived at the National Institutes of Health in Bethesda, Maryland in 1969 and joined Dr. Warren Strober. Together we began a long relationship and conducted much study into the causes of celiac disease. Dr. Strober and I were two of the founding members of the Medical Board of Advisors for CSA. It is a privilege to be speaking to you at this assembly of the CSA.

Basics of the Celiac Condition
Celiac sprue is a disease that I have spent 25 years studying. It is frequently called celiac sprue but is called as well by many other names. Gluten-sensitive enteropathy is the name that I have preferred for many years because the term gluten-sensitive enteropathy told me precisely what we were dealing with. We are talking about a disease in which there is sensitivity to gluten and it is an enteropathy. The term enteropathy means a disease of the small intestine. In the old days, before we had a clue as to what was going on in this condition, some of the earlier names included nontropical sprue as well as idiopathic steatorrhea. In idiopathic we have the medical term that means, "we don't know." If you have a problem disease for which we don't know the cause, we call it idiopathic, and steatorrhea means "fat found in the stool," the essence of malabsorption, hence idiopathic steatorrhea.

Celiac disease is a gastrointestinal disease. I think this is an important point. Celiac disease is not a systematic disease although there may be some things that happen systematically [that is throughout the body]. In the gastrointestinal disease business we have other conditions with a systematic illness. But celiac disease is a disease of the small bowel and not of any other organ system. The major characteristic in celiac disease is an abnormality of the lining of the small intestine. This abnormality results in trouble with digestion--specifically with absorption of food. All the consequences basically deal with this one primordial process which is villus shortening and abnormality of the lining of the intestine. The gastroenterologist's view of the human body, if you will, is a sphere with a hole through it. The hole represents the digestive tract traversing the body from one end to the other, and anything in the digestive tract is still technically not in the body, just passing through. "Getting into the body" requires digestion in the lumen and transport across the lining into the bloodstream. Getting across the lining is the seminal problem in celiac disease.


The other key point about the condition is that it is caused by gluten. It is one of the few conditions in which we have a very precise mechanism and a nasty product, because if you take gluten away, everyone with the disease eventually becomes a normal individual. Gluten is bad for people with the disease, but is not necessarily bad for people without the disease. Gluten is a glycoprotein. Gluten is actually insoluble. It is what makes dough "doughy." If we did not have gluten, we would have "no dough" and then we would be poor.

Making the Diagnosis of Celiac Disease
How do we make the diagnosis of celiac disease? Of course everyone is going to have a different clinical history. The physician has to think about celiac disease because you cannot see what you are looking for. For the patients who have a terrible problem with all of the sequelae--malabsorption and everything that happens as a result of malabsorption--the diagnosis is usually easy to make. The problem in those patients whose disease spectrum is such that the disease is relatively modest--for example, there are some patients who only malabsorb iron. They may present with anemia. The internist may just think it is iron loss from either menstruation or a polyp in the colon. There are lots of different reasons for anemia which are not celiac disease--it might take a while for those patients to be diagnosed. Some patients present with thyroid problem, a broken leg, or something else not directly related primarily to the GI tract, so it may not be easy to make this diagnosis.

Once we establish the diagnosis of celiac disease, we still have to make sure that we have this diagnosis because there are things that can masquerade as celiac disease that really are not celiac disease. So we have to confirm the diagnosis one way or another. Today, with the endomysial antibody test, it is a little easier. We do not necessarily have to put people through a gluten challenge as we use to.

Celiac disease is a condition that begins in two different presentation modes. We have children who have this disease. They are weaned, they start eating the cereals and all of the sudden, you have a child that is not thriving anymore who has elements of malabsorption with one parameter or another. They get cranky, have diarrhea and they start to lose weight. And then the diagnosis is ultimately established.

Or you can have a person who is completely healthy until they are 20, 30, 40, 50 or maybe even older. And so in adult life, you can have a patient presenting for the very first time with a condition which by all intents and purposes hasn't been present [from their perspective] up until that point.

Celiac disease is a genetically determined disease. We will review some of the genetic studies during this talk. We believe strongly that you have celiac disease from the moment you are born. It only manifests, however, after ingesting gluten. So with babies and newborns without gluten in their diets, there is no problem. Once gluten goes into the diet, the disease begins to be manifested.

The curiosity is that even with ingestion of gluten some patients may have no symptoms until later in adult life. We do not know why this is. We believe that this disease is actually under-diagnosed. For instance, in Europe, if you go to Galway in Ireland, one in three hundred people have celiac disease. And yet if you go to certain parts of America, perhaps one in four or five thousand people has celiac disease. And the question is, what is the real incidence. We believe that the incidence is probably between those two numbers. Again, we also believe that it is being under-diagnosed. It is possible there are a lot of people walking around with subliminal symptoms. These people are not quite sick, but they are not quite 100%, and nobody knows really what to do with them as they visit their doctors with new prescriptions. I think a lot of those people are going to turn around and be undiagnosed celiacs.

Celiac Disease as a Malabsorption Syndrome
When you have malabsorption, a lot of bad things happen to you. What happens in malabsorption is you malabsorb all nutrients. There are three basic nutrient components beside trace minerals and vitamins. We basically have proteins, carbohydrates and fats. In celiac disease, there is a malabsorption of all of these. This is because in essence, it is not like a patient with pancreatic disease when they have fat malabsorption primarily. The problem is that whatever you are ingesting cannot get into your body because the lining of the intestine is inadequate; you have malabsorption of everything. You have seen the pictures of babies in Africa with big bellies; that is protein malabsorption. From celiac disease you can get:

  • protein malabsorption
  • muscle weakness
  • edema
  • malabsorption of vitamin D which is a fat-soluble vitamin
  • hypocalcemia from which you will start to twitch and your bones will get thin
  • vitamin A malabsorption will affect the vision with night blindness

So there are a lot of different elements to malabsorption. I have already mentioned that iron deficiency anemia is one of the presenting problems. And so weight loss, diarrhea, steatorrhea, problems with trace vitamins are hallmarks of the malabsorption element. Just think that any of those elements may be malabsorbed in different amounts. So that is why the clinical syndrome may be so different in different people. Some patients may be very sick and others may not be so sick. That is one of the things that makes it so difficult at times to make the diagnosis. I know that sometimes we get mad at our doctors; "they don't quite get it." But, you have to be persistent.

So how do we make the diagnosis? Well, I have already said that the first thing we have to do is think about the diagnosis. You have to consider the possibility that malabsorption is playing a role in whatever process is going on in a particular patient. And then you have a variety of diagnostic modalities that are available. These include the laboratory and radiology.

The small bowel loops in celiac patients are dilated and fluid-filled. And that fluid is there because it is not being absorbed adequately. So when you see this kind of picture, this is characteristic of malabsorption. It is not, however, diagnosis for celiac disease. Anybody with any kind of malabsorption condition will have this particular kind of picture. So the patient coming in with this and having some intestinal problems is not going to be diagnosed as a celiac just by this kind of X-ray alone.

The hallmark, the gold standard for diagnosis remains the jejunal biopsy. Celiac disease is a disease of the small bowel. And so of all the things that we do to investigate patients, if we really suspect the diagnosis, this is the gold standard, the small bowel biopsy. And very frequently, it will be the first thing that I'll do if I am really strongly suspicious that this is the diagnosis. it saves a lot of time and effort because you do the biopsy and "bingo," you have a diagnosis pretty quickly.

The small bowel is characterized by finger-like projections called villi. These little fingers are lined by cells that are called columnar epithelial cells. And all of the action of absorption occurs in these cells. Absorption of food from the intestine isn't passive absorption. There is a lot of work that the cell has to do to bring the food into the body, and to do all of this work, the cell has to be healthy. In celiac disease, it is not healthy. So that's why we get into all of the trouble with malabsorption. When we take a biopsy and get a picture of flat villus architecture, we suspect celiac disease. The tall finger-like villi stick out into the lumen--the inside of the intestine. They increase the surface area for absorption so that our intestines are like two or three football fields worth of surface area.

In the small bowel biopsy of a celiac patient, the villi are totally gone. This is a loss of the villus architecture. If you look at the surface, the epithelial cells look sick. They are unable to process and absorb and do the things that we need them to do. The lamina propria are the cells underneath the surface. We see here round cells. Those are plasma cells and lymphocytes and these are the guys that normally battle germs but in this case, gluten involves them in a battle with epithelial cells. The key point that I make in my research work is that celiac disease is an immune system gone amuck.

We have discovered that there are certain antibodies in patients with celiac disease that are very interesting. Gliadin is the bad component of gluten. When we hear people talk about gliadin, what we are really talking about is a purified part of gluten that is bad for celiac patients. [Incidentally, we did some experiments years ago in which there were a number of people in California who were trying to engineer wheat without gluten. It turned out that we couldn't do that. We did engineer wheat without alphagliadin, which is the toxic part of gluten, but it turns out that nature is so smart that its beta, gamma and other gliadins were equally toxic. So forget it, we still have to avoid gluten in the diet.]

The antigliadin antibodies are non-disease specific. You can see antigliadin antibodies in the blood stream of even normal people. Antigliadin antibodies are not pathognomonic for the celiac patient. Antigliadin antibodies go away after a gluten-free diet, therefore, if you have a patient who is not doing well, you could check their antigliadin antibodies. And if they are very high, maybe they are getting gluten without recognizing it or are cheating on the diet.

And then there are the endomysial antibodies. As a diagnostic tool, this is a very good tool. It is effective in helping us make a diagnosis in maybe 95% of the patients. This test can be used to screen many people.

There are some people for whom a diagnosis of celiac disease is made, and they don't do well. So why is that? The usual reason is that they are not sticking to their diet. There was an article in the Journal of Digestive Diseases in which a group in one of the European countries where there's a lot of celiac disease, she that most people who don't do well are still getting gluten in their diet. So that's the number in thing: gluten-free is essential for a clinical response.

The other possibility, for perhaps not doing well, is that they do not have celiac disease at all. And what do I mean by that? Well, there are lots of things that look like celiac disease but are not. So we as physicians have to be detectives. This is especially true in the pediatric group and less so in the adult group. The condition of tropical sprue is caused by bacteria that are damaging to the intestine. The small bowel biopsy looks similar to that of celiac disease and those patients have steatorrhea.

And there are certain immune deficiency diseases with malabsorption. In these patients, bacteria will create an intestinal lesion that looks quite similar. People who are starving get very short villi. Gastroenteritis which is another childhood disease, or cow's milk allergy or soy protein allergy and even giardia can cause blunting of the small intestinal mucosa. So if someone comes in with diarrhea, malabsorption and they get a biopsy and the diagnosis of celiac disease is made and they don't do well, these alternative diagnoses must be considered.

Patients with celiac disease may have thyroid disease as well. We know that the most threatening problem for celiac patients is lymphoma, typically of the small bowel. This [the condition of lymphoma] seems to be much more prevalent in European countries and not as prevalent in American celiacs. It is a complication and it is one of the reasons why we stress to our patients how important it is to maintain a total, strict gluten-free diet. We feel that lymphoma of the small bowel is diminished as a complication by good control of the disease [strict adherence to the gluten-free diet]. There may be other problems genetically associated with celiac disease such as dermatitis herpetaformis and diabetes mellitus.

The Organ Culture Model System for Research

One of the problems in doing research on clinical disease is that use of patients or their tissues is a prerequisite for the research. So the concept is that if you want to do experiments, to discover and gain insights, it is important to have a controlled environment which you can study in the laboratory. Thus, we spent some years developing a model system for study of celiac disease. The model system required that intestinal tissue from patients with celiac disease, grow in a system gluten-free or with gluten. One could then manipulate the environment and study the impact of those variables in a controlled environment.

So, for example, when a patient is diagnosed, they go on a gluten-free diet, the intestine gets better, lots of parameters change and they improve. That is very useful information. Wouldn't it be nice if you could take that condition and put it into a system that you could then dissect out and try to individually study different elements that contribute to the condition?

The first challenge was to develop a model system in which we could actually do that. The system we utilized is called an organ culture model system. It is predicated upon the ability to take tissue and grow it in a liquid medium. The difficult aspect of this approach as opposed to cell culture is that in organ culture the tissue is organized. For example, a slice of liver or a slice of the small intestine: there is a surface, epithelial cells, there's a villus structure, there's a lamina propira. It's organized; it is acting as an organ system as opposed to free-floating cells which are not organized.

The breakthrough came from the development which allowed one to take organ material and culture it in an in vitro system. One of the problems is that if you have an organ, you have to nourish it. And if you have a large organ like the intestine, the brain, the liver or the heart, blood has to flow into it in order to nourish it. And so in an in vitro or an explant system, you don't have blood flowing. So you have to be able to nourish it by bathing it in solutions.

The question was, "how do you do that?" We did it by taking the small pieces of intestine and culturing them on grids and having nutritional material flow around them and bathe them in oxygen.

The concept for the model was, "if you take a celiac patient and give them a gluten-free diet, the intestine gets better. Can we do that in vitro? The research model is predicated on the question. We quantified three easily measurable parameters. One was the function of the cell which was measured by studying the enzyme activity at the surface. The enzyme activity on the surface is just a marker, think of that as a metaphor for function. And in this case, the marker is called alkaline phosphatase and was the marker of the integrity of the cells we chose to study.

The other two parameters that were studies were the ordinary morphology; just looking at his material--what did it look like after you cultured it with or without gluten. And then the third parameter that we studied was the electron microscopy--the ultra microscopic appearance of the cell's brush border. And so those three parameters form the elements of this model system. Our first consideration is the level of alkaline phospatase in the tissue just after we have taken it out of the patient. It is 140 units, a low number; the normal number should be more like 400 or 500. So it is very low, and is reflecting that the tissue is in bad shape. Next, we cultured the organ explant for forty-eight hours in the absence of gluten--that is, we put it on a "gluten-free diet."

The level of alkaline phosphatase is now 420! This was a very exiting finding; that organ tissue improved in forty-eight hours and became healthy. How did it do that? It did that because it was an organ that is growing. And the cells at the base if the villi called crypts are the factories; they are making new cells. And so the factory is in fact healthy. The problem isn't the factory, the problem is that when the cells get up into the lumen, they get "knocked off" by gluten. In this environment, without gluten, those cells in the crypt were coming up and becoming normal. In the parallel culture with gluten in the medium, there is no improvement from baseline. So here we have the functional element of the model system. They morphology parts of the model parallel the functional elements.

Using this system model, we did a lot of different experiments. For example, we cultured these organ explants in the presence or absence of cortisol. Now why cortisol? Cortisol is an immune-ablative material. What do I mean by that? If you give cortisol to someone, the immunity will come down. We use it in patients with transplants, for example, to keep transplants from rejecting. So it cuts the immune system. We postulated that all those immune cells in the lamina propria must be doing something. The antigliadin, antiendomysial antibodies must be doing something. So let's cut those out by using cortisol. And we discovered that by adding cortisol and by cutting the immune reactivity of these little explants in vitro, we were able to show that gluten didn't adversely impact the tissue recovery. So the final pathway is not gluten per se.

Now we are getting to the mechanism of the disease: the mechanism is an immune effector system. The army that is actually causing the damage seems to be an immunological one. We believe that there is an immune background to the condition, and that id we can get rid of the immune system, we can get rid of the bad effects of gluten. That conclusion comes from the data of this in virto system.

Now why do we get celiac disease--anyway? I will digress just a moment. We don't know. But we do know that there are patients with diseases like lupus who are genetically predisposed to their disease. That disease can get turned on by an infection of a virus. And so people looked for viral infections in celiac patients and discovered that a great number had this adeno-type virus number 12 antibody in their bloodstream. And so the question was, "why would that be?" It turns out that this virus has certain amino acid sequences that are very similar to the sequence of gliadins. A mechanism for infection with this virus could be how you switch on the disease in terms of clinical manifestations.

The concept of such switches is predicated on genetics [inherited gene patterns]. We knew based on other studies, that patients with celiac disease have immune responses that are exuberant. We also postulated that their immune responses were to a specific antigen--in this case, gluten. Why this immune response? There are these genetic markers called HLA genes. They have a great biologic significance. There is a lot that they are involved with including transplantation matching and so forth. But there is also a connection with the so-called immune response gene and cell surface receptors. Basically what these genes represent to celiacs--and incidentally in a lot of other conditions--are metaphors for disease susceptibility. They represent the ability for something to come into the body and do something if you have the gene; or the ability to do nothing if you do not have the gene.

Let me finish by putting together a disease model based on the data at hand. We knew patients with celiac disease had abnormal immune responses. We knew that HLA genes were connected with immune response genes. Therefore we looked for HLA genes in celiac disease and found that in fact there is a major increase of certain immunological markers. Nearly 90% of celiacs have a particular set of HLA genes as opposed to only 20% of normal people having these genes. We believe these genes predispose one to develop celiac disease. There is recent data supporting these ideas. The concept is simple. On the surface of the epithelial cell we have two products--an HLA and a celiac gene product. These two genes are required to manifest the disease. If you have one or the other alone, it won't happen--you won't have the disease. That is why in families some members may or may not have the disease because they may not have inherited both of these genes.

When you have these two genes together, they form a receptor complex. Gluten can bind to that receptor complex. When it binds to this receptor complex, it initiates an immune response. The lymphocytes, and you know from reading about lymphocytes that they are the generals of the immune system, respond. And so this gluten which now becomes immunogenically reactive as a result of binding to this surface receptor complex stimulates a local immune response. Now we have proven that it does that because we have proven that there are antigluten antibodies made by the organ explants in culture; we know about antiendomysial antibodies and we know that we ablate the responses with cortisol and other immune-ablative materials.

From this research and its results, we have the specificity that is required by this model system. In other words, this isn't just somebody going out and shooting randomly, this is somebody going out and killing this epithelial cell in the intestine. Remember that is the target organ. So we have to have specificity of this immune response, and this specificity is rendered by the target that is on the surface of that cell, gluten bound by the receptor complex!

 

 

CSA Library Series
CSA Library Series is a collection of articles that pertain to celiac disease and dermatitis herpetiformis. Most of these articles have appeared in CSA’s quarterly newsletter, Lifeline, which all CSA members receive. Historic articles included in these resources may or may not include updated notes. Updated information indicated in red type. Articles represent the work of the author.