Celiac Disease in Adults

    Celiac disease, whether called gluten-sensitive enteropathy or non-tropical sprue, is one of a number of diseases that disrupt the absorptive surface of the small bowel.  The result with celiac disease:  a classical malabsorption syndrome for the patient.  Malabsorption can be defined as an inadequate extraction of nutrients from ingested food to maintain health.  Celiac disease, although not a common disease, may have such subtle presentation as to be missed by the physician not adequately informed of its many clinical manifestations.  

    Malabsorption syndromes similar to celiac disease have been noted by physicians for thousands of years.  Recorded observations from Artaeus, the Capadocian of the second century, A.D. described a disease with fatty stools and weight loss.  At that time, the malady was typically ascribed to an impairment of digestion.  

    Few scientific references appear in the literature on celiac disease until the late 1800s when Samuel Gee described the "celiac affection" in referring to a distinct type of diarrhea and malnutrition in infants.  His description of these cases included many of the clinical features recorded in present literature.  Bennet's observations in 1932 recognized the same disease and symptoms in both children and adults.  Dicke in 1950 demonstrated the toxic effect of gluten, the gliadin fraction in wheat protein, after observing a decreased incidence of celiac disease during World War II in Holland when wheat products were in short supply to the general population.  At about the same time, with the invention of the Crosby capsule, it was demonstrated through small bowel biopsies that celiac disease in children and adults was the same condition.  The term celiac sprue was coined to cover the condition of both age groups.

    Further studies have isolated gluten as a 10- to 15-percent extractable protein portion of wheat.  Gluten itself has been subdivided into gliadin with 15,000 molecular weight fraction and glutenin.  It is the gliadin that appears to contain the active factor causing the small bowel damage.  A further sub-fraction of gliadin, fraction 3 with a molecular weight of less than 1,000 is also thought to be an active factor.

    The mechanism by which the gliadin fraction actually damages the mucosa remains unclear.  Acid peptides in the gliadin fraction may damage the villi of the small intestine either because of a lack of certain brush border peptidases or by an immunologic reaction unrelated to any particular enzymes.  

    Several immune factors operate in celiac disease.  Among these are marked increases in the Iga/Igm synthesis when precipitated by gluten exposure.  In addition, antigliadin antibodies have been found in jejunal aspirates and in stools.  Abnormal functioning lymphocytes also have been demonstrated. 

    Frequency of celiac disease is greater in blood relatives and most studies show that it is present in roughly ten percent of parents of patients, sixteen percent of siblings, and twelve percent of children.  However, these are percentages that vary with the criteria used to make the diagnosis and certainly there exists a relatively mild form of the condition for which both biopsy and biochemical testing would be needed to reveal more adequate data for evaluation and diagnosis.

    Although childhood and adult forms of celiac disease involve the same mucosal defect, there are several aspects of the adult condition that differentiate it from the pediatric form.  When the gluten-free prescription diet is maintained, adults may have remissions although the abnormal mucosal changes remain and can be demonstrated on biopsy in some cases.  Children who maintain the gluten-free prescription diet appear to return to completely normal mucosa on biopsy examination.  The level of gluten ingestion [tolerance of gluten] seems to vary with individuals as a minute amount of gluten may precipitate symptoms in one person, but not in others.  Similarly, it may take longer for mucosal changes to appear in some individuals; once the condition is diagnosed, it is not advisable for the patient to deliberately ingest any amount of gluten at any time.  Typically, adults present with only one malabsorption defect such as fat malabsorption, carbohydrate malabsorption or protein malabsorption.

    The main presenting factors in patients with celiac disease includes anemia--either iron deficiency, macrocytic or a mixed anemia.  This variation, along with diarrhea, is typically the most common presenting factor of the disease.  In lesser numbers, abdominal pain, aphtous ulcerations of the mouth secondary to vitamin deficiencies, growth failure and failure to thrive, tetany, dysphasia and a subfertility and sexual immaturity may also be presenting factors.  The most common physical findings are evidence of weight loss, abdominal distention, edema from hypoproteinemia, hepatomegaly, and hypotension.

    Formerly, [perhaps twenty years ago--the early 1980s] diagnostically, studies in the evaluation of a patient suspected of celiac sprue would include general screening studies of malabsorption with pro-time and serum carotene.  Carbohydrate absorption was measured with a d-xylose absorption test.  Fat malabsorption was studies with a 72-hour pooled stool collection for quantitative fecal fat.  For practical purposes, protein malabsorption was not generally tested.  At this time, the typical medical evaluation includes a series of immunologic studies; the standard diagnostic test is the small bowel biopsy from the proximal jejunum with any of the available capsules that can be passed into the jejunum under fluoroscopic control.  The expected changes are shortening or complex flattening of the villi columnar to cuboidal change of absorbing cells and infiltration of the lamina propria with plasma cell lymphocites. 

    Treatment is entirely dietary, the gluten-free prescription diet with the elimination of all cereal grains.  When treatment failures occur, it is the adequacy of the dietary program that should be first inspected.  Improvement of the diet can be expected within a few days in many cases, although some patients may require months of treatment before improvement.  There is no significant mortality rate associated with celiac disease as long as both children and adults adhere strictly to the gluten-free diet for life.  As Samuel Gee stated back in the 1880s, "but if the patient is to be cured at all, it must be by means of diet."     

Whatever Gluten-Free Is--Make It So! 

        A diet excluding common grains containing offensive gliadin is the cornerstone treatment for celiac patients.  Such a strict gluten-free diet is recommended irrespective of the presence of perceived or known symptoms.  However, maintaining a strict gluten-free diet is not a simple matter.  Small amounts of gluten capable of causing a relapse or prolonged problems [for a few hours, a few days, or for several or many months ahead] have been identified in a variety of unsuspected sources.  And, what is "gluten-free" in one standard may appear to be "gluten-containing" by another standard [point of view or personal experience, interpretation of a chemical assay, or professional judgment].

        To date, there is no definition as to what amount of gluten in the diet might be tolerable for the general celiac population.  In addition, several researchers continue to feel that each patient is unique and different and with unique and differing needs.  In essence, the notion is supported that we are dealing with a series of celiac conditions that have some common threads but with differing needs and expressions of the illness from patient to patient.  Thus, one size would never fit all.  Secondly, there still appears not to be an agreement on the definition or standard of "what is gluten-free."  What appears to one patient to be a tolerable food or ingredient and is then claimed to be an appropriate food or ingredient for the gluten-free diet may cause an intolerance and not be an appropriate food item to be included in the diet for the next patient.

        Since the identification of gluten [selected defined orders of amino acids within the gliadin fractions of gluten] as the etiologic factor in celiac disease, a strict gluten-free diet has become the recommended management for celiac patients [and those with the condition of dermatitis herpetiformis].  The very strict gluten-free diet is suggested for both symptomatic and asymptomatic patients.  At this time, it continues to be the standard practice to treat all patients with the celiac condition by dietary means.  But the products with and without offending gluten, how much gluten, and which products to allow or not allow in the diet are still questioned.  Nevertheless, present evidence strongly supports that the restriction of gliadin and related prolamin should be complete for all patients.

        The data available show that for celiac patients who have been on a gluten-free diet for five years or more--the risk of developing one of the cancers over all sites within the body is not increased when compared with the general population.  However, the risk is increased in those patients using a reduced or restricted gluten diet or [a gluten-containing diet] or normal diet.  There appears to be an excess of cancer of the mouth, pharynx, esophagus, and particularly a higher risk of lymphoma [T-cell lymphoma, a tumor of mucosal T-cells, possibly the intraepithelial T-cell component].  In addition to the cancer potentials, strict dietary compliance is recommended to avoid other long-term risks associated with celiac disease:  poor general health or slowly deteriorating general health; developmental retardation; infertility; new areas of malabsorption; bone disease; deterioration of the celiac condition during pregnancy; taking on other autoimmune conditions.

        Present evidence gives strong support for advising all celiac patients [no matter at what age or level with the illness] to adhere to a strict gluten-free diet for life.  Even a small or minute contamination in a food should be avoided.  While the knowledge base for foods and food choices may not yet be available to us, the patient is best advised to take extreme care in developing food choices and the base foods allowed in their own personal prescription diet.  Patients are advised to find the 20 to 30 foods known to be gluten-free that fit personal needs and that patient's "brand" of the illness.  For most celiacs, a careful consideration for medications, their ingredients, fillers, and sealers may also be necessary.  For the very sensitive patients, personal care and planning may need to be extended to include contaminated containers for foods, common items for use on the skin, and selected contact materials within the environment.  A precocious education along with a well-regulated plan for self-management needs to be put together and organized within a definition of self that allows the individual the determination to take on and succeed with a diet appropriate for them and their version of the celiac condition.

Diarrheas With Celiac Disease

    Generally, diarrhea is a dysfunction of either the small or large intestine.  Often abdominal cramps, bloating, or gas accompany diarrhea.  However, these symptoms may or may not be present for the celiac patient and may or may not be helpful in establishing a diagnosis of celiac disease or a problem that occurs with the condition.  The presence of diarrhea does not pin down the location of a problem and may not be related to the cause.

    Diarrhea may occur for several reasons.  When the intestine has excessive secretions, it is known as secretory diarrhea, a situation in which hormones or substances cause the intestine to secrete excess amounts of fluid.  This is a more unusual type of diarrhea and is typically associated with rare tumors that secrete these hormones.  The diarrhea that travelers get, tourista, like a cholera, is a form of secretory diarrhea.  Often persons with secretory diarrhea have voluminous, watery diarrhea.  Secretory diarrhea does not improve when the person fasts or goes on a specific food withdrawal.  The diagnosis of the cause of secretory diarrhea is usually made by a special blood test specific to the hormone.

    A second form of diarrhea is called osmotic diarrhea.  The cause is unabsorbed materials that draw water into the intestine and overwhelm the capacity of the colon to absorb water.  Examples of substances that may not be absorbed in the intestine include beans or a commercial laxative product such as milk of magnesia.  Most of these substances are made up of carbohydrates, sugars, and starches.  Eating a carbohydrate that is not absorbed may produce several symptoms in addition to diarrhea.  The bacteria present in the gut ferment the unabsorbed carbohydrate which produces gases and a series of substances irritating to the colon.  The end results of carbohydrates not being digested are gas, cramps, and perhaps diarrhea.  When more carbohydrate materials are ingested, the symptoms are increased and worsened.  A person with carbohydrate intolerance will typically have no symptoms unless an offending food with a specific carbohydrate to which the person is intolerant is ingested.

    One of the more commonly encountered carbohydrates mal-digested is lactose of cow's milk, a condition referenced as lactose intolerance.  Consuming lactose, the sugar in milk, has about the same effect as eating beans in individuals who do not have the enzyme to digest it.  Similar symptoms are produced by sorbitol, a sweetener that is commonly added to such sugar-free products as chewing gum and hard candies.  Bran can produce similar symptoms because it, too, is a non-absorbed carbohydrate.

    Individuals have varying levels and different tolerances and/or symptoms related to each of these substances.  A typical example, some people may have more gas or cramps and diarrhea when eating beans; some may have none.  The fact that persons with several of the intestinal disorders [including celiac disease] often also have varying or selected carbohydrate intolerances can camouflage symptoms for celiac disease as well as for other underlying diseases or immune disorders.

    Another form of diarrhea is caused by acute or chronic inflammation in either the large or small intestine.  A bacteria or a virus usually causes acute diarrhea.  Many types of bacteria cause diarrhea.  Some bacteria cause diarrhea by increasing intestinal secretion, but others cause inflammation.  Patients with this type of inflammatory diarrhea often have a fever and may see blood in their stools.  Most of the acute diarrheas last only a few hours or a few days at most.  Complete recovery is the rule.

    A chronic inflammation causes diarrhea in persons with conditions such as ulcerative colitis, inflammatory bowel disease, and Crohn's disease, all of which have symptoms similar to celiac disease.  Ulcerative colitis may cause the diarrhea to have blood in it because of inflammation of the lining of the colon.  Crohn's disease tends to be associated with more cramping than ulcerative colitis.  Both conditions may be associated with symptoms seemingly unrelated to the intestines.  They may present with joint or back pain, skin rashes, growth impairment, and liver disorders.  Diagnosis may include radiological examination or examination with a color scope.  Treatment includes specific medications aimed at decreasing the inflammation.

    An abnormal motility, or movements of the intestine, can also cause diarrhea.  An abnormal movement pattern is most typical for persons with irritable bowel syndrome [IBS].  Persons with IBS may have diarrhea, constipation, abdominal pain, bloating, gas or any combination of these symptoms at varying levels.  Often persons with IBS have had many tests which are unrevealing.  They may have had surgeries or be on varying medications with no relief.  Names such as spastic colon or colitis are used improperly as they imply inflammation of the colon.  Persons with IBS have no inflammation, but do have a sensitive gut.  Although stress, stimulants such as coffee, and lactose intolerance can aggravate IBS, many persons are not able to pinpoint factors that irritate their condition or cause symptoms.  Fortunately, IBS does not lead to any serious complications, though it can be uncomfortable.

    In celiac disease, when the stool contains excessive fat, it is referenced as steatorrhea.  Steatorrhea may cause diarrhea by all of the possible mechanisms, but is a much more specific diarrhea, as it narrows down the site of abnormality.  Steatorrhea is caused by either a lack of one of the necessary digestive enzymes or is the result of an abnormal surface in the gut lining with the result that fat is not absorbed in the intestine.  When the digestion of fat is normal but the absorption of fat and other food nutrients is abnormal, the surface of the small intestine is diseased [or affected].  There are more possibilities in children than in adults.  The most likely possibilities in adults are infections, Whipple's disease, tropical sprue, lymphoma, and celiac disease [non-tropical sprue].  The primary infections that can cause damage over a prolonged period are parasites, the most common being giardiasis.  Generally this causes more watery diarrhea, but with severe infestation, steatorrhea can result.  Giardia is present everywhere, but typically can be contracted through well water or mountain streams.  The diagnosis is made by stool examination or inspection of fluid from the small intestine.  A specific antibiotic treatment results in rapid recovery.  

    In summary, the typical mechanisms of diarrhea are increased secretion, increased osmotic content of the stool, inflammation of the bowel, and altered motility.  In celiac disease, the primary concern in diagnosis is with steatorrhea.  

Celiac Disease Revisited

    Just go on the gluten-free diet and you'll be cured--is a common message given the newly diagnosed celiac patient.  But eating gluten-free is not that simple, so putting the diet into practice is the challenge.  The good news, of course, is that most of the complications of celiac disease can be avoided by a careful adherence to a self-managed prescription gluten-free diet that is adapted to and for a specific individual.  

    Roll call: who did it?  How celiac disease occurs depends on intolerance to gluten, the major component of the endosperm in grains.  The major constituents of gluten, which are basically carbohydrate-containing proteins, are glutenins and gliadins.  And it is within gliadin that we find the fraction that contains the element, which triggers the toxic reaction; it has maminor constituents as well and has other proteins that have nutritional value:  lipids and carbohydrates.  But it is the specific fraction of gliadin that is the problem for the celiac patient.  Gliadins as a family are alcohol soluble and glutemine and proline rich.  Glutemine and proline are important amino aids in the diet and they are constitutents of both plant and virtually all-animal cells.

    It's those amino acids that don't have their ducks in order.  Gliadin can have as many as forty or more components.  Finding the toxic fractions has been a 20-year job of researchers.  Only alpha-gliadin has been implicated in celiac disease and the specific antigen that is the problem, is a small peptide with a molecular weight of about 1500.  A peptide is just a string of amino acids, the building blocks of proteins, which are strung in a chain.  Finding the exact configuration of the protein might be helpful in learning how to block the immune response to the toxic gliadin fractions in persons who have celiac disease.

    It's the immunology in celiac disease that is deranged.  Of the several theories regarding the onset of celiac disease, there now appears to be no question that the condition is an autoimmune disease in which the immune system is altered.  The immune system is probably altered as a genetic variant; that is, those persons who have celiac disease have something different about their immune system from those persons who do not have the disease.  But how that variant triggers the toxic interaction with gluten remains a challenge to research and study for the future.

    The damage in the lining of the jejunum of the small bowel can occur within hours either after ingestion of gluten or even more rapidly if gluten is placed directly on the mucosa, the lining of the bowel.   The experiment is done by actually putting gluten on the small bowel in a targeted place and then serially biopsying that site or adjacent tissues.  The results show that there was a progression of injury where the gluten has been placed in the small bowel.

    IgA is a protein that is secreted by the body to protect itself against bacterial injury.  In celiac disease, IgA against gluten is deposited in the base membrane of the intestinal eptithelial cell, the lining on which the cells sit.   It appears to be the first alteration that occurs when the bowel is exposed to gluten.  It is this immune response that occurs very rapidly after gluten is presented to the lining cells of the small bowel.

    There are other findings such as elevated serum IgA levels and marked IgA production by the lymphocytes in the small intestine.  There are alterations of the marker proteins, the DR-antigens of the cells of the small bowel, especially in the crypts.  There is a hyperproliferative response, an increase in the turnover of cells.  There is a risk of lymphoma in untreated patients or in patients who do not give compulsive attention to the gluten-free diet.

    Disease friends that may be associated with celiac disease.  There are several associated conditions that may not link to celiac disease, but may appear concurrently with the celiac condition.

    Thyroiditis.

    Addison's Disease, an adrenal insufficiency.

    Pernicious Anemia, an anemia associated with a B-12 deficiency, but sometimes caused by excessive antibodies to protein carriers.

    Antibodies in the blood reduce autoimmune thrombocytopoenia, a disorder in which platelets, the clotting cells in blood.

    Sarcoidosis.

    Insulin-dependent Diabetes Mellitus.

    Down's Syndrome.

    Iga Nephropathy, an autoimmune kidney problem related to an interaction IgA with the membrane in an autoimmune form.

    IgA deficiency itself, the inability to make IgA predisposes to celiac disease and has an important implication related serological testing for celiac disease.  If your IgA is low, you have a potential for having normal tests even if you have celiac disease.    

    It's in your bloodline to stay.  There is clearly a gene association for the person with celiac disease.  There is a common susceptibility locus [marker] on chromosome six.  That means that scientists can do screenings and find what is known as naplotypes, i.e., markers associated with chromosome six that identify the presence of a susceptibility to take on celiac disease.  The marker is associated with changes in the HLA status of the patient; the HLA markers are proteins on cells that distinguish one person from another.   While the markers do not identify every single case of celiac disease, there is clearly a stratification of these markers in people who have celiac disease compared to people who don't.  

A Brief Overview of the Gastrointestinal System

    A review and understanding of the gastrointestinal system helps with the understanding of celiac sprue enteropathy.  The stomach is the storage organ in which food goes after passing through the esophagus; it is in the stomach where food is prepared for digestion.  It is first broken up into small particles and mixes with stomach secretions of gastric juices containing hydrochloric acid and pepsin.  It is here that protein is broken down into peptones.  The churning motions of the walls of the stomach help these processes.

    These end food products are then propelled through the narrow passage of the pylorus into the duodenum, the first part of the small intestine.  Here fat is broken down by the bile from the liver; secretions from the pancreas and the intestine further break down carbohydrates into simple sugars; the protein peptones are broken down into amino acids.  

    These products are moved down into the jejunum of the small intestine.  The jejunum is about six feet long and is the primary site for the absorption of carbohydrate, protein, and fat products into the bloodstream.  This process continues in the ileum which is about 18 feet long.  

    Water is important to all of these digestive processes.  The amount of fluid that is drunk each day is between two and three quarts.  The gut is remarkably efficient in using fluid.  Only about a pint is left in the food residue in the colon.

    Diseases and conditions of the gastrointestinal system.  The common problem of heartburn is caused by a reflux of acid liquid from the stomach to the esophagus.  Tiny ulcers may occur in the stomach or gastric ulcers may occur in the intestine.  

    An adequate blood supply is critically important to the absorption process and can be deprived of the needed nutrient chemicals by a lack of absorption across the membrane of the intestine into the blood.

    Infections of a viral origin may cause tiny patches of inflammation within the intestine which impair the absorption and transporting of nutrients.  An irritable bowel and diarrhea may be caused such an infection.  An enteritis infection sometimes leads to a chronic effect with an inflammation that impairs and restricts the gut.

    There may be inflammation of the sigmoid flexure of the colon or of the diverticulas--the little distended sacs which occur in the colon.  Ulcerative colitis may occur in selected patients, about 15 per 100,000 population.

    Probably the most common problem is constipation which calls for an increase of fiber [roughage] in the diet and adequate exercise.  

    Celiac Sprue Enteropathy.  In celiac disease the absorption in the duodenum and jejunum is reduced--leading to malabsorption.  These are the areas of the small intestine in which the nutrient and products of digestion are transported across the membrane and into circulation.  The surface area for absorption is markedly increased by the folds [valvulae] of the small intestine and through the villi and micro-villi.  When these surfaces are lost, there may be only 1/200th of the surface area remaining for absorption.

    This kind of malabsorption leads to dehydration, wasting due to loss of the body-building blocks of carbohydrates, proteins, and fats and often to a general weakness and lack of energy.  A patient may have 20 stools a day and large quantities of gas due to the large amount of residue in the intestine.  This causes a distended abdomen; bones may be affected because neither calcium nor vitamin D is absorbed.  A lack of vitamin K can lead to bruising, bleeding problems, and mouth sores or soreness.  There is often a general sense of feeling ill.

    In the small intestine, new cells for the villi are lost in one day instead of the usual three.  The crypts between the villi become larger and the villi become shortened or do not exist.  There are more plasma cells which increase the size of the lamina propria, the layer of connective tissue beneath the surface epithelium.  

    A biopsy of the small intestine of a celiac patient will show that villi have disappeared, crypts have expanded, plasma cells have increased, and eosinophillic cells and lymphocytes have decreased.

    The condition of celiac disease may appear at any age.  It is thought that about 8% of cases are inherited.  Other cases are not entirely genetic, although they appear to also be genetically related.  

    In children up to the age of 5, there is likely to be poor growth with abdominal distention, irritability, muscle wasting, and abnormal stools.  In the 5- to 15-year old patient, there may be muscle wasting, macrocytic anemia, a sore red tongue, and cramps in the fingers.  The patient may not grow as rapidly as peers and may develop typical sex characteristics of puberty at a later time.

    In the adult there is likely to be a slow to very slow onset with diarrhea, abdominal cramps, weight loss, tetany, anemia, vomiting or anorexia as possible symptoms.  One study showed the following symptoms to be most common among non-diagnosed celiac patients:  diarrhea, lethargy, abdominal distention, discomfort or pain with cramps, weight loss, anorexia, muscle cramps, constipation, edema, and vomiting.  

    Symptoms that alert a physician to suspect possible malabsorption include weight loss, steatorrhea, bloating, diarrhea, anemia, bleeding and bruising, osteoporosis, and tetany.  These symptoms result from the failure of digestion, failure of absorption, and the obstruction of lymphocytes.  

          Getting to Know Celiac Sprue?

             What is Celiac Disease?  Celiac Sprue (celiac disease) is an inherited disorder, which manifests itself at any age throughout the life cycle.  It is often diagnosed when the child begins consuming cereal products or at any time in adulthood after nutrient malabsorption and associated problems.

             In adults, symptoms relate to the following intrinsic factors, (genetic, immune) and environmental factors, (virus and gluten interaction) to cause the enteropathy commonly known as celiac sprue.  More data must be collected and more long-term research carried out before relationships can be established with certainty and links verified with the onset of the disease.

             Common names for Celiac Disease.  The terms generally used include the following:  celiac sprue (CS), celiac disease, the celiac condition, the celiac affection, celiacs, non-tropical sprue (NTS), idiopathic steatorrhea, gluten sensitive enteropathy (GSE), malabsorption syndrome, gluten intolerance, gluten sensitivity, the celiac syndrome, intestinal infantilism, Gee-Herter’s disease (or Gee Herter’s syndrome).  All names refer to the same problem—the inability to tolerate the gluten found in wheat, barley, rye, oats and a series of grains including selected varieties and/or contaminated millet and buckwheat.  Most foreign, and especially British references, spell celiac as coeliac.

             In celiac disease, the small intestine lining is damaged by a protein fraction of gliadin found in gluten (gliadin is the alcohol soluble fraction of gluten).  Since two of the major functions of the small intestine are digestion and absorption of nutrients, the damage results in malnutrition for the individual involved.  Research and the monitoring of hundreds of patients indicate that healing of the small intestine will only occur when the offending gliadin is removed from the diet.

             Celiac Disease Defined.  By definition, the condition of celiac disease results in a malabsorption problem (a malabsorption syndrome).  The effect of gliadin should not be confused with an allergy or hypersensitivity. 

             Celiac Disease is a condition in which the following situations occur for the patient:

                       1)      malabsorption of nutrients in that portion of the small                         intestine (the jejunum) which is damaged;

                   2)      a characteristic though not specific lesion of the small                          intestinal mucosa;

                    3)      prompt clinical improvement following withdrawal of                             selected cereal grains from the diet.

               Celiac Disease is seen as a pathologic response to dietary antigens.  The condition should not be seen as a food allergy since it is not an idiosyncratic reaction to food proteins; it is not mediated by IgE;  and, it is not typified by rapid histamine-type reaction (typified by broncho spasm, urticaria, etc.).

           Since World War II, there has been much interest in and considerable research directed toward celiac disease, but the mechanism by which gluten damages the lining of the small intestine is still not understood.  What is special about the gliadin fraction of gluten is that it causes small intestine mucosa damage in celiac patients.  There are several considerations under study, but the answer is generally seen as unknown.

             External factors which might be important in the development of celiac disease, such as the amount of gluten consumed or the occurrence of minor bowel infections. are difficult to study.  In recent years, it has been found that the number of new cases of childhood celiac disease detected has been decreasing; however, the onset of the problem in adults has been increasing.  It is thought that diagnosed cases may represent about 1 per 2500 while the potential for non-diagnosed cases may be close to 1 per 250. 

             The evidence accumulated has led to the development of several theories that are put forward to explain mechanisms that induce symptoms and signs of celiac disease.

             Peptidase Deficiency Theory.  This is a theory of the 1950s, which is referred to as the “missing peptidase” hypothesis.  The basis was the observation that digestion of gluten or gliadin with purified pepsin, trypsin and papain did not destroy the toxicity of these wheat fractions.  This was interpreted as an indication that toxicity was due to a small peptide resistant to proteolytic cleavage.  The concept supported was that celiac patients lack a specific peptidase. 

               Despite intensive investigations, this hypothesis has not been validated; the activities of the various digestive peptidases are normal or almost normal in the intestinal mucosa of celiac patients on a gluten-free diet.

             Primary Immune Defect Theory.  This theory suggests that celiac disease occurs because of an immunological reaction against gluten, which damages the small intestine.  That is, the intestinal defense mechanism of the celiac patient, normally used against harmful bacteria, viruses, or parasites, are brought into action against gluten, a substance which does not trigger this effect in non-celiacs.  There is considerable evidence that immune reactions to gluten do occur in celiac patients.  However, research to this point in time, is not conclusive as to whether an immunological abnormality is the underlying cause of celiac disease.

             Lectin Theory.  It has been suggested that a primary abnormality in the composition of the surface glycoproteins on epithelial cell membranes result in exposure of distinctive sugar residues that selectively bind toxic gliadin fractions in celiac sprue patients.  The gliadin fraction might then damage the intestinal epithelium, much as cytotoxic plant lectins damage cells after binding to their surface.  That plant lectins are capable of damaging intestinal epithelium has been clearly demonstrated.  However, at present there is little evidence that gliadin fractions have lectin-like activity directed against eptithelial cells isolated from normal intestine or from intestinal biopsies from treated or untreated celiac patients.  One postulate represents that when both lectins and lecithins are present together with a plant protein that an interaction occurs which is then damaging to the crypts and villi of the small intestine.  And, it is also thought that  some peptins may serve as lectins.  While not a tested or proven theory, it is a concept, which is often considered when making selections for the clinical diet of the diagnosed celiac patient. 

             Intestinal Cell Abnormality Theory.  This concept suggests that celiac disease occurs because celiac patients have a specific abnormality of the sheet of cells known as the epithelium, which lines the intestine.  Although experiments have increased the understanding of how the small intestine works, there is no conclusive evidence of the primary abnormality in celiac disease.  It is difficult to be certain whether the abnormality is a basic cause of the disease, or whether it is merely a result of the disease.  

          Virus Theory for Celiac Disease.  Recently, there has been research directed to celiac disease as being linked to a rare virus and from time-to-time, we see this theory popularized in the press.   

             It is theorized that human adenovirus 12 [(Ad12) infection] may be the trigger that sets off the autoimmune chain reaction that causes the syndrome.  The epidemiology of Ad 12, when isolated from the human intestinal tract, is unknown.  However, evidence from both England and the United States indicates it may offer the first step in finding new treatments for monitoring the condition.

            Dr. Martin Kagnoff at the University of California-San Diego thought there might be a viral link because studies of identical twins have shown that not all genetically susceptible persons develop the disease.  Dr. Kagnoff took a protein found in grain that was known to activate the disease, alpha-gliadin, and fed its amino acid sequence into a computer data bank.  Less than one percent of the screened proteins met the criteria, but human Ad 12 filled the bill.

             In a joint study with St. Bartholomew’s Hospital, London, a study of eighteen celiac adults and thirteen celiac children from England were examined for evidence of prior viral infection.  Thirty patients from San Diego were also examined for Ad 12 neutralizing antibodies.  Such antibodies do not react to anything else and therefore they provide an independent measure of past exposure.

             Eighty-nine percent of untreated adult celiac patients showed evidence of infection and between 5 and 33 percent of treated adults.  Almost 31 percent of treated child patients had also been exposed.  Control groups showed less than 0.05 percent had the antibody.

             Thus, it is thought that virally encoded protein sequences might possibly play a role in the initiation of celiac disease.  There is a probability of an immunological cross-reaction between the virus and alpha-gliadin.  It has been theorized that the pathogenesis of the disease seems to involve immune mechanisms, but the role of the antibodies and the T-cells in producing the damage has not been clear.  However, this joint study shows that the amino acid sequence shared by alpha-gliadin and the Ad12 protein can function as an antigenic determinant.

             Celiac Sprue as an Immunologic Disease.  The most commonly supported theory held in mainstream medicine is that the condition is a genetic, inheritable disease linked to genetically transmitted histo-compatibility linked to cell antigens (HLA DR3-DQ2, DR5/7, and DR4-DQ8).  It is a disease characterized by damage to the mucosal lining of the small intestine known as villous atrophy.  This damage to the villi and the crypts results in malabsorption, which in turn produces malnutrition. 

             The mucosal damage of celiac sprue is almost certainly mediated by the immune system.  It likely is associated with antibodies to gliadin, reticulin and/or enndomysial (smooth muscle) proteins.  It is likely that the antibodies probably do not directly cause the damage, though they may be signals for cell-medicated immunity.  The cellular immune system (T-cells) are thought to produce the actual enterocyte injury, but only when gluten-type prolamins are present.

             The nature of the intestinal injury of celiac disease is that it is insidious and slow to develop.  It is directly related to ingestion of certain grain prolamins, especially gliadin proteins such as found in wheat, barley, rye, and oats.  The common result is the loss of intestinal villi in the upper small intestine, the jejunum, with loss of absorptive function and inflammation.  In most cases the condition is reversible if the injurious protein is excluded from the diet.  In most cases the condition is reversible to completely normal bowel histology and function following strict adherence to the gluten-free diet. 

             The major damaging proteins of the prolamin class are found in cereal grains.  These proteins are rich in proline and glutamine, especially those with amino acid sequences of Pro-Ser-Gln-Gln and Gln-Gln-Gln-Pro.  These particular sequences or analogues are high in triticums, the wheats.  The central proteins to be avoided  include wheat glutenins, barley hordeins, rye secalins and oat avenins.  Corn zein and rice oryzenin, which have a different order of amino acid sequences, are not found to be toxic to celiacs and may be included in the clinical diet, [the prescription diet]. 

 Signs and Symptoms of Celiac Disease

             A typical case of celiac disease probably does not exist.  Each patient exhibits a variable combination of symptoms of variable severity.  Each patient exhibits their own complex, complicated pattern and combination of overt and covert symptoms which are unique to them and their version of the illness. 

            In children, the symptoms become apparent 3 to 5 months after first consuming gluten-containing foods although for some few cases, the interval may be as short as one month.  Many experts on infant feeding advise that solid foods should not be introduced to the baby’s diet until nearly five months old and that gluten-containing cereal should be avoided for the first six months of life. 

             The celiac, but otherwise normal baby, thrives until gluten is introduced to the diet and then begins to refuse feedings and fails to gain weight.  The child may gradually become irritable or listless and develop a large abdomen.  The stools become abnormal, perhaps large, pale and offensive, or be representative of a loose-like diarrhea.  Stools generally float because of the high content of air and fat.  The child may also vomit from time-to-time or exhibit forceful projectile vomiting with the consumption of selected foods.  Many children lose weight or have a failure to gain weight and the buttocks become flattened.  Some few children become quite ill with acute diarrhea and dehydration. 

             Older children with more subtle symptoms of poor appetite, poor growth and anemia are much more difficult to diagnose as there are many other reasons for failure to grow in childhood.  Clinical symptoms often diminish or disappear during puberty (adolescence), although biochemical or morphologic abnormalities may persist.  More active symptoms will again reoccur in early adult life. 

             Adult celiacs who visit physicians do so, not only because of abdominal symptoms, but also because of such things as breathlessness, fatigue or just because they feel more tired at the end of the day than they used to.  The difficulty for the doctor is that almost any chronic illness may start with these symptoms.  And the difficulty for diagnosis increases when other vague and non-specific symptoms are added to the profile. 

             In the case of celiacs, the breathlessness may be due to malnutrition or the development of anemia, which is a deficiency of the oxygen carrying pigment, hemoglobin, in the red blood cells.  Because of the many and varied ways that celiac disease can present, the diagnosis frequently is not considered and the diagnosis may be delayed.  This is particularly the case in those persons who present primarily with constitutional symptoms, anemia or osteomalacia, neurological complaints, psychological disturbances, infertility, or growth disturbances.

             The most common clinical symptoms for adults with onset of celiac disease usually include some of the following:  weight loss; chronic diarrhea; abdominal cramping and bloating; intestinal gas; abdominal distention; muscle wasting or muscle weakness; lack of energy; and, low level to chronic fatigue.  Often patients will have only soft stools and do not have diarrhea; a small number of patients may actually have hard stools or be constipated.  Some patients may represent anorexia and others maintain a voracious appetite. 

             Other symptoms include:  changes in the oral mucosa and other tissues due to vitamin deficiency (Example:  a smooth tongue and cracks in the corners of the mouth); mineral deficiency such as iron deficiency anemia or muscle cramps in the hands and legs secondary to calcium deficiency; edema due to low blood protein level; and, malabsorption of fat-soluble vitamins A, D, and K.   A decrease in these vitamins may lead to the following problems:  with the loss of vitamin A—night blindness and follicular hyperkeratosis; with the loss of vitamin D—osteomalacia (leading to muscle cramps, bone pain, fractures, tetany); with the loss of vitamin K—decreased ability to clot blood.  There may also be hemorrhagic manifestations; patients may bleed into the skin or mucous membranes or may develop menaturia, epistaxis, and gastrointestinal bleeding.

             The malabsorption of other nutrients such as carbohydrates, protein, salts, and water may lead to some of the following situations:  dehydration; electrolyte depletion; growth retardation; edema; anemia; peripheral neuropathy (a numbness and tingling in the fingers and toes); central nervous system and spinal cord lesions (affects primarily the cerebellum and balance); personality changes (especially common in children with sprue); selected children may become unable to concentrate, be irritable, cranky and have difficulties with mental alertness and memory function; the same process may occur in adults.

             Before removal of gluten from the diet, celiac patients may also experience neuropsychiatric symptoms, including mood changes, irritability, and depression.  The diagnosis of celiac disease is easily missed in patients whose primary symptoms are neurologic or neuropsychiatric—especially if gastrointestinal symptoms are not prominent. 

             The damage to the mucosa lining of the small intestine is characterized by a shortening and flattening of the villi—at least in the upper part of the small gut, the jejunum.  At one time it was thought there was atrophy, but more researchers are indicating that this may not be the case (that there is no real atrophy but rather rapid loss of cell surface with the result even with increasing cell recovery, it is unable to keep up).  This research interpretation indicates the following general concepts:  the loss of absorptive surface cells of the mucosa results in failure to digest and absorb food from the small intestine into the blood.  The concentration of gluten is highest in the upper part of the small intestine, just beyond the duodenum, where the absorption and the bowel damage occurs.

             Celiac patients demonstrate great variability in their real and apparent “sensitivity” to gliadins.  Some may experience adverse intestinal function promptly after ingestion of only minute amounts of gluten; however, most experience a delayed and insidious detrimental effect on intestinal absorption after repeated exposure to small amounts of gluten protein. 

             Women with celiac disease may experience abnormalities in menstruation, particularly amenorrhea and delayed menarche; some disturbances in fertility have been observed.  Typically, these are improved by exclusion of all gluten from the diet.  In men, impotence and infertility can be seen.  Malnutrition may contribute to these changes, possibly through abnormalities in centrally mediated hormone regulation. 

             All of these clinical problems are due to the inability of the small intestine to absorb nutrients normally. The variation in the combination of symptoms exhibited by persons with clinical sprue is thought to be related to the variable amount of intestinal damage and the length of time that nutrientabsorption has been abnormal. 

 How Celiac Disease is Diagnosed

             Although there may be many clinical signs and laboratory tests indicating probable malabsorption, the “blue chip” means for diagnosing celiac disease is by small intestine biopsy (the jejunal biopsy) and response to the clinical diet (the gluten-free diet).  Thus, there is then the critical importance of the high false-positive rate of diagnosis, with an unnecessary institution of the gluten-free diet, when the biopsy is not performed. 

             Several of the noninvasive screening tests provide information that can assist decision-making when the diagnosis is in doubt.  None of the noninvasive tests currently available should be substituted for the small intestine mucosal biopsy in establishing a diagnosis. 

             In the biopsy, a small flexible tube is passed down the throat through the stomach and duodenum and on into the upper end of the small intestine, the juncture of the duodenum and jejunum.  At the end of the tube is a metal cylinder containing a port (hole) and knife device; suction is applied through the tube that draws a piece of the intestine lining into the port.  Activation of the knife cuts off the small piece of mucosa within the capsule and closes the port.  On removal of the tube, the tissue sample is taken from the capsule, processed, and examined under a microscope.

             Many celiac patients are currently doing endoscopic evaluations that involve passing a larger tube to inspect areas of the intestine; then biopsies can be taken through the endoscope.  It is quicker than the capsule procedure and can be done in 10 to 15 minutes; and, it is generally seen as more consistent for both the patient and the physician.  The drawback of the endoscopic biopsy is that the specimens are smaller, may be difficult to orient for execution, and may be sampled in a somewhat higher location in the small intestine.  All of this may make microscopic examination more difficult.  Therefore, it is important that multiple endoscopic biopsies be taken from a part of the bowel as far into the intestine as the endoscope can be passed. 

              The difference between normal bowel tissue and that found in celiac patients is remarkable.  In celiacs, the normal finger-like projections (villi) that increase the absorptive surface area of the small intestine are partially or totally absent.  The brush border, microvilli, which normally appears on the surface of the villi, is substantially flattened or reduced.  Enzymes normally located on the brush border are drastically reduced.  Lactase, the enzyme responsible for splitting milk sugar (lactose) so it can be absorbed, is an example of one of these brush border enzymes that may be reduced or not presently active.  The decrease in lactase explains why some untreated celiac sprue patients may not be able to tolerate milk products.  The small bowel biopsy samples of persons with dermatitis herpetiformis often show similar damage.

             The second essential part of the diagnosis is improvement on a gluten-free diet.  Elimination of all wheat, barley, rye, and oat products and any of their derivatives is essential.  In selected cases several of the dozens of varieties of millet and buckwheat and all contaminated millet and buckwheat must also be omitted from the diet. 

            A diagnosis of celiac sprue can be made through careful consideration of three major sources of information which comprise a database: a case history; physical examination; and, laboratory findings.

             History of the disease.  Important considerations include the following areas:

                a.   symptoms such as diarrhea, fatigue, cramping, weakness,                      bloating, flatus.  Has there been a history of dehydration,                      electrolyte depletion or acidosis?

              b.   stools—foul, floating, clay-colored, light tan or gray;  highly                       rancid and frothy;  not all patients have diarrhea, some                       complain of constipation.

                 c.    in children—failure to grow, weight loss or failure to gain                        weight.

               d.   emotional status—irritability and inability to concentrate.

               e.  although  gastroenterological  symptoms   may  be  present,                          the  most   distressing  problems may involve other organ                     systems.  Examples: refractory iron deficiency anemia; back                        pain as a result of a collapsed lumbar vertabrae;                       osteopenic bone disease; hyperparathyroidism; and, amenorrhea. 

             Physical Examination.  Depending on the presentation of symptoms, the physician will check for some of the following items:

                 a.  emaciation; a decrease in muscle mass and fatty tissue;

                   b.  pallor (due to anemia);

                    c.   hypotension (low blood pressure);

                     d.  edema (due to low levels of protein, (albumin) in the blood;

                  e.  dermatitis herpetiformis (skin lesions);

                      f.   easy bruising (due of lack of vitamin K);

                      g.   bone or skin and mucosa membrane changes due to vitamin                           deficiencies;

(potassium is to soft tissue what calcium is to hard tissue).

h.   protuding or distended abdomen (intestine dysmotility);

                        i.    loss of various sensations in extremities including                                          vibration, position, and light touch (vitamin deficiency);       

                    j.    signs of severe vitamin/mineral deficiencies which may                             include the following:

                             1.      diminished deep tendon reflexes;

2.      signs of tetany (muscle spasms) denoting severe magnesium and/or calcium deficiency;

3.      bone tenderness and bone pain due to osteomalacia;

             Laboratory Findings: Some of the following tests may be used in determining malabsorption syndromes:

            a.       blood tests;

1.      serum carotene;

2.      nutritional anemia;

a)      iron deficiency anemia;

b)      vitamin B-12/folate deficiency;

3.      clotting time (indicator of vitamin K deficiency);

4.      protein (serum albumin; transferrin);

5.      minerals (calcium, magnesium, zinc);

6.      electrolytes;

7.      cholesterol;

            b.      stool examination;

1.      24-hour weight of stool (abnormal if greater than 300 grams);

2.      presence of increased fat; (stool which contains more than 6% of the amount of fat consumed).

   c.     tolerance or measures of digestion/absorption tests;

     1.      lactose tolerance test;

 2.      D-Xylose test;

                       d.      immunologic tests:

           1.      endomysiac antibodies;

  2.      gliadin antibodies;

  3.      reticulin antibodies;

                        e.       the jejunal biopsy;

             Further investigations are usually concerned with excluding other conditions (finding out what is not occurring), assessing which nutritional deficiencies are present and sometimes finding out about the severity of the deficiency.  And with this observation, learning which nutrients are being absorbed and which are not.

             In summary, the diagnosis of celiac disease is made by demonstrating impairment of small intestinal mucosal function; documenting the presence of the mucosal lesion by intestinal biopsy; and, observing a clinical improvement on withdrawal of all gluten from the diet. 

  Protein Toxicity in Celiac Disease

               The detection of certain proteins can be very important to the health and well being of persons who have the immune disorder, celiac disease.  These proteins are toxic to persons having celiac sprue, causing significant physiological harm and potential premature death.  Current detection methods are expensive, complex, and not totally accurate.  Also significant, these methods are not easily usable by the general public.  Further, at the present time, there is no requirement for the identification of these toxins in all food products.  Unfortunately, the offending proteins are included in many foods because of the extensive use of wheat, its derivatives and similar grains in commercial food processing.

             The grain wheat has been raised as a food source for over eight thousand years.  It is now one of the most important grains grown and basic to the food needs of much of the world.  Wheat is important because of the protein gluten, which makes it easy to work with in baking bread and related products.  This protein makes bread dough sticky so that it stretches or has visco-elasticity.  When dough is made with ground wheat, water, and yeast, the carbon dioxide produced by the yeast-related reactions is trapped in small bubbles within the dough, making the dough rise and the bread more palatable.  Other ground grains such as barley, rye, oats, corn, and rice do not rise well when used in baking because they contain poor quality gluten or differing patterns of gluten.  Gluten is made of high-glutamine and high proline storage proteins [prolamins from a compositional standpoint].  This makes gluten proteins in dough cohesive and extendible.

             Besides the use of wheat in baking, it has become important in flavoring mixtures and as binders in foods and drugs.  This is a problem in many countries because wheat is normally not named specifically on labels and because the grain or flour being used as a flavoring or binder may often change.  Instead of being labeled as wheat or other grain product, food processors and manufacturers use names such as “modified food starch,” “vegetable protein,” “textured vegetable protein,” “hydrolyzed vegetable protein,” or “vegetable thickener,” when preparing labels for commercial foods, such as meats, condiments, canned goods and some dairy products.  This is a major problem in food selection for the small segment of the population that has the condition, celiac disease.

             Within the United States, celiac disease appears to be most common in persons of European descent, though there are cases in all ethnic groups.  Celiac sprue is hereditary in the blood line, but recent evidence shows that environmental factors may be required to trigger the disease.  An immune response to human intestinal adenovirus serotype 12 (Ad12) may be an important contributing environmental factor.  The Elb protein of the Ad12 has virtually the same amino acid sequences as alpha gliadin.

             In the person with celiac disease, products derived from wheat, which contain proteins commonly called gluten or gliadin, cannot be digested because of an immunological reaction to the toxic prolamins in these proteins.  Products produced from barley, rye, and oats cause the same immune reaction because of prolamins that have similar amino acid sequences.  Wheat, however, is the only grain that contains all of the toxic prolamins.

             The continued consumption of the toxic prolamins in a person who is affected with celiac sprue causes a reaction that destroys the villi in the small intestine [the jejunum], resulting in malabsorption of vitamins, minerals, proteins, amino acids, sugars, and fats.  In children, this malabsorption causes bone problems because of lack of calcium, abdominal distension, vomiting, muscle wasting, and failure to properly grow and develop.  In adults, it results in tiredness, weight loss, anemia, cramps, and swelling of the tongue.  Also in both groups, there is malnutrition and risk of intestinal carcinoma.  Symptoms of celiac disease can appear any time in life, but in most adult cases, it is likely that the symptoms have been sub-clinical before becoming fully apparent.

             There is only one accurate way to test for celiac sprue, a biopsy of the small intestine [jejunum].  A tube is inserted into the throat until it reaches the jejunum where a minute piece of the intestine is removed.  The villi on the sample are examined under microscope for flattening, a result of the immune response to the toxic prolamins.  If flattening of the villi is found, then the person is taken off all foods containing gluten.  Another biopsy is performed several weeks later, which should show regenerating villi and prove that celiac sprue is the cause of the symptoms.  The only cure is a strict, well-defined gluten-free diet directed to the specific needs of the patient being treated.  This single factor is why clear, exact labeling of food products is important for the self-management of the prescription diet for celiac disease.

             Foods labeled as containing “modified food starch,” “vegetable protein,” “texturized vegetable protein,” or “vegetable thickener” remain a serious problem, since it is not clear whether these products have a gluten [prolamin] content.

             There are two protein groups, which compose gluten.  First are gliadins, which are soluble in alcohol/water solutions.  The second group is the glutenins, which are not soluble in alcohol/water solutions, but are soluble in some salt solutions. 

             The gliadin proteins are separated into Alpha, Beta and Gamma gliadins, which contain intra-molecular disulfide bonds.  These bonds link one part of a polypeptide chain to another.  The Omega gliadins do not contain disulfide bonds, which means that they do not contain cysteine [or probably methionine] in their primary structure.  The Alpha, Beta and Gamma gliadins are toxic, whereas, Omega gliadins are non-toxic.

               There are two amino acid sequences that have been found to be toxic in the Alpha, Beta and Gamma gliadins:  -Pro-Ser-Gin-Gin- and –Gin-Gin-Gin-Pro-.  [Pro=proline, Gin=glutamine, Ser=serine].  The Omega gliadins do not contain these sequences.  These exact sequences may not be contained in other grains, but other grains may contain very similar sequences.  [Note the listing in the Table].  The sequences are not found at all in maize defined as corn [with the protein, zein] or in rice [with the protein, oryzenin].

             Because of the high content of glutamine in gluten, it was thought that glutamine might be toxic by itself, but this was found not to be so.  It has been found that glutamine is important to toxicity because when glutamine is hydrolyzed to glutamic  acid, gluten was no longer toxic.  It is likely that this is because of the cleavage of key amino acid sequences.  Also, another observation that glutamine could not be toxic on its own is because maize [corn] contains as many as six glutamines in a row, and they have not been found to be toxic.

             The glutenins are divided into groups, high molecular weight (HMW) and low molecular weight (LMW).  They differ from the gliadins in that they contain intramolecular and intermolecular disulfide bonds.  The intermolecular bonds link many polypeptide chains together instead of just linking polypeptides into linear chains, even though many glutenins are linear.  This factor may also contribute to the visco-elasticity of gluten in baked products.

                  For many years, it was believed that the glutenins were not toxic, but it has been discovered that they do contain toxic amino acid sequences.  The LMW glutenins contain both toxic sequences, -Pro-Ser-Gin-Gin- and –Gin-Gin-Gin-Pro-; whereas, the HMW glutenines contain only the –Pro-Ser-Gin-Gin- sequence.