Author : Henry J. Binder, M.D. Professor of Medicine Yale School of Medicine
2008-07-28
2008-07-28
Introduction
Celiac Disease is a common autoimmune disorder of the small intestine with manifestations that may also involve a variety of different organ systems (e.g., bone, blood) resulting in a significant spectrum of symptoms. The autoimmune response has a known environmental trigger – gliadin - the subfraction of gluten responsible for initiation of the tissue damage that occurs in Celiac Disease. Gluten is found in many grains, including wheat, rye, and barley. Celiac Disease was once considered primarily a pediatric disease associated with diarrhea and so-called malabsorption (i.e., decreased absorption of one or more nutrients) but is now known to be present in perhaps 1% of the world-wide population, across all ages, who may or may not have intestinal symptoms or who may not have any symptoms at all. | ||
| Digestive system and small intestine. Source: NIDDK |
History of the Disease and its Causes
Celiac Disease was initially described by an English pediatrician, Samuel Gee, in the late nineteenth century who believed that this disease primarily, if not exclusively, affected children. The relationship of Celiac Disease to gluten intake was established in the Netherlands in the late 1940s when the Dutch physician Dicke observed that children with Celiac Disease improved during the German occupation of the Second World War but relapsed after liberation. He correctly surmised that the absence of wheat during the war was responsible for the improvement of these children and their subsequent relapse at the end of occupation was occasioned by the reintroduction of bread (wheat) into the diet. Subsequent studies established that the toxic property in wheat is gluten (also present in rye and barley) and specifically, its subfraction, called gliadin.Several other names, besides Celiac Disease, have been used to describe this condition. The term, Non-tropical Sprue was coined to distinguish Celiac Disease (when it occurred in adults) from Tropical Sprue, a disease that was initially thought to occur primarily in expatriates from temperate climates residing in tropical countries (e.g., the Caribbean, India) and who developed symptoms (usually diarrhea) either while living in these areas or upon their return to temperate climates. Thus, it was believed that Celiac Disease (in children) and Non-tropical Sprue (in adults) represented the same entity -- for many years the term Celiac Sprue was frequently used to emphasize that this condition could affect both children and adults. After Celiac Disease was found to be associated with gluten ingestion, the term “gluten-enteropathy” was adopted to emphasize the importance of gluten affecting the intestine. Today, the term Celiac Disease is commonly used to refer to the condition in both children and adults.
In the 1960s, the development of small intestine biopsy techniques using a variety of suction biopsy instruments (prior to the advent of flexible endoscopes) led to several important observations in Celiac Disease. These included: 1) The lining of the small intestine is distinctly abnormal when examined under a microscope; with the removal of gluten from the diet, the small intestine returns toward normal (and indeed, can become completely normal in appearance); 2) The proximal small intestine is more affected by Celiac Disease than the distal portions of the small intestine, and as nutrients and micronutrients are absorbed in a segmental manner, this distribution of abnormality determines nutrient and micronutrient deficiencies in Celiac Disease; 3) Re-introduction of gluten will result in a return of the microscopic appearance of the small intestine to its original abnormal state and will often result in the recurrence of the presenting complaints. Since the abnormal appearance of the small intestine is not unique to Celiac Disease, for many years its diagnosis required a typical small intestinal biopsy appearance; improvement of both symptoms and appearance on small intestinal biopsy while on a gluten-free diet; and reappearance of symptoms following challenge with dietary gluten. Development of symptoms after the reintroduction of gluten is no longer required to establish the diagnosis of Celiac Disease.
Genetic factors are also very important in disease development, as gliadin must bind to one of two proteins (called HLA-DQ2 or HLA-DQ8) on certain white blood cells (lymphocytes) to initiate its toxic effects on cells in the intestinal tract. As a result of this interaction, various cytokines are released and cause damage to small intestinal epithelial cells (see below). The presence of these two genes (HLA-DQ2 and HLA-DQ8), which may be found in approximately 35% of the population, does not necessarily mean that the individual has or will have Celiac Disease. In contrast, individuals who lack the HLA-DQ2 and HLA-DQ8 genes never develop Celiac Disease.
Serological Studies
The past one to two decades have brought significant change in the
understanding of Celiac Disease, largely as a result of the development
of serology (blood) tests that can identify individuals with a high
likelihood of having the disorder. These serology tests, particularly
tissue transglutaminase (tTG) IgA antibody and endomysial antibody
(EMA), and an expanding research base have resulted in major
breakthroughs in our understanding of Celiac Disease. The tests may be
positive in milder forms of the disease are highly but not 100%
specific, meaning a positive test does not definitively indicate Celiac
disease. Several studies have established that the sensitivity of the
tTG assay, an ELISA assay that is less expensive and less affected by
observer variability, is excellent (in statistical terms, the test is
more than 96% sensitive, while its specificity is 94%). In contrast, the
EMA assay, an immunofluorescent assay, is subject to observer
variability, but has sensitivity and specificity approaching 99%.
A few additional comments about the available celiac serology tests require comment. First, since these antibody assays represent the presence of a so-called Immunoglobulin A (IgA) antibody, individuals who are IgA globulin deficient may not have a ”positive” assay even though they have Celiac Disease. Studies have established, however, that partial IgA globulin deficiency will not result in a false-negative test, but individuals with complete absence of serum IgA globulin should be assessed by an assay using an IgG antibody. Second, there are other celiac serology assays – antibodies to gliadin – that often are performed but whose sensitivity and specificity are too low to provide meaningful data. Additional serology assays are being developed -- in the future, it is likely that Celiac Disease will be evaluated with these newer and hopefully better antibody studies.
Population studies primarily using the serologic tTG antibody assay have established a very significant incidence (0.5-1.0% of the population) of Celiac Disease in all major population groups around the world. In the United States this incidence, primarily based on studies using blood donation samples, is 1 in 133 individuals (or 0.75%).
A few additional comments about the available celiac serology tests require comment. First, since these antibody assays represent the presence of a so-called Immunoglobulin A (IgA) antibody, individuals who are IgA globulin deficient may not have a ”positive” assay even though they have Celiac Disease. Studies have established, however, that partial IgA globulin deficiency will not result in a false-negative test, but individuals with complete absence of serum IgA globulin should be assessed by an assay using an IgG antibody. Second, there are other celiac serology assays – antibodies to gliadin – that often are performed but whose sensitivity and specificity are too low to provide meaningful data. Additional serology assays are being developed -- in the future, it is likely that Celiac Disease will be evaluated with these newer and hopefully better antibody studies.
Population studies primarily using the serologic tTG antibody assay have established a very significant incidence (0.5-1.0% of the population) of Celiac Disease in all major population groups around the world. In the United States this incidence, primarily based on studies using blood donation samples, is 1 in 133 individuals (or 0.75%).
Clinical Presentations
Despite this substantial incidence, the majority of patients with positive tTG assays have minimal or no gastrointestinal symptoms or may be symptom-free. The occurrence of so-called classical symptoms of Celiac Disease – diarrhea, steatorrhea (increased amounts of fat in stool, i.e., fat malabsorption), and weight loss – is rarely seen today in adults with a diagnosis of Celiac Disease. Instead, many of these individuals have a variety of non-gastrointestinal symptoms.Anemia: Anemia is increasingly being identified as the presenting problem that leads to a diagnosis of Celiac Disease. In Celiac Disease (or any condition associated with altered intestinal absorptive function) anemia may be caused by diminished absorption of one or more critical mineral or vitamins (i.e., iron, folic acid and/or Vitamin B12). The presence of a persistent iron-deficiency anemia despite use of oral iron (especially in a man or a post-menopausal woman) strongly suggests the possibility of Celiac Disease and should lead to a tTG assay. It is important to note that iron (and folic acid) are exclusively absorbed in the duodenum, the area of the small intestine which is most affected in Celiac Disease. Treatment of iron-deficient anemia in Celiac Disease is with oral iron supplementation (until iron stores are corrected) and a gluten-free diet.
Bone disease: A variety of bone diseases that are caused by diminished availability of calcium are not infrequently diagnosed in Celiac Disease. Osteopenia, osteoporosis, and osteomalacia are the specific bone diseases that may be found. The initial presentation of these conditions will either be a pathologic fracture, i.e., a fracture of a bone in the absence of trauma, or from findings on a ”routine” bone density examination (usually taken to look for early signs of osteoporosis). Calcium absorption also occurs primarily in the duodenum and is enhanced by Vitamin D, whose absorption may be diminished by fat malabsorption (or steatorrhea) in Celiac Disease. Oral calcium and Vitamin D as well as a gluten-free diet are appropriate treatment of bone disease occurring in Celiac Disease. There are certain diseases that seem to result in a higher rate of Celiac Disease. Such conditions include diabetes mellitus (type 1), Down’s syndrome, and Turner’s syndrome. The explanation for these associations is not known. The accurate diagnosis of Celiac Disease in diabetes mellitus is important as diarrhea may occur in patients with both type 1 and type 2 diabetes mellitus, from causes other than Celiac Disease.
Other presenting symptoms that may be caused by or associated with Celiac Disease include short stature; neurologic symptoms (especially peripheral neuropathy); abnormal liver function tests (often a reflection of non-alcoholic fatty liver); peripheral edema due to hypoproteinemia; and irritable bowel syndrome. In addition, an uncommon skin condition, Dermatitis Herpetiformis (or DH) may be identified in patients with Celiac Disease. To the trained observer, the skin lesions of Dermatitis Herpetiformis are very characteristic; their presence should lead to a duodenal biopsy.
Diagnostic Studies
Today,
the diagnosis of Celiac Disease is established by the presence of a
compatible history; an abnormal duodenal biopsy consistent with Celiac
Disease; and clinical improvement and reduction in the tTG assay
following the removal of all gluten from the diet (a gluten-free diet).
Duodenal biopsy: The diagnosis of Celiac Disease requires a mucosal biopsy from the initial portion of the small intestine. For the past two decades (or so) these biopsies have been almost universally obtained with an endoscope. During the endoscopy study, the esophagus, stomach and proximal duodenum are visualized and examined. Endoscopic biopsies can be obtained much more easily and quickly than biopsies obtained with suction biopsy instruments. Unfortunately, the endoscopic approach yields small pieces of biopsy material, which may be technically difficult to orient and therefore difficulty to read. Patients with an elevated EMA and/or tTG antibody study should have a duodenal biopsy to establish the diagnosis of Celiac Disease. However, if patients with a suggestive history do not have positive Celiac serology, these patients should also be referred for endoscopic biopsy of the duodenum.
Initially in the development of small intestinal biopsies in Celiac Disease, it was generally believed that the only biopsy appearance consistent with Celiac Disease was that of a so-called “flat biopsy.” This appearance represents the inflammation resulting from the presence of gliadin in the small intestine causing a) villous atrophy (a loss in the characteristic peaks and valleys of the intestinal lining); b) crypt hyperplasia (elongation of the valleys); and c) increase in intra-epithelial lymphocytes within the epithelial cells lining the villi (more inflammatory cells in the so-called surface cells). Any biopsy that was not so severely damaged was usually considered not to represent Celiac Disease.
During the past several years there has been a significant reassessment of the small intestinal biopsy appearance in Celiac Disease. Today, mucosal biopsies that are only partially abnormal may still be diagnosed as Celiac Disease. New criteria establishing levels of intestinal damage as assessed microscopically were developed by an English gastroenterologist, Michael Marsh. This classification may deem positive biopsies with only an increase in so-called intra-epithelial lymphocytes in surface epithelia cells, as well as the more classic cases, with severe and total villous atrophy with crypt hyperplasia.
The small intestinal biopsy appearance of Celiac Disease is not, by itself, diagnostic of Celiac Disease. There are several other diseases that may present with biopsies that resemble Celiac Disease. These include Tropical Sprue; Crohn’s Disease; Collagenous Sprue; Common variable immunodeficiency; Gastrinoma; Intestinal Lymphoma; Intolerance to Soy; and Giardiasis. The clinical presentation and the response to a gluten-free diet will differentiate these conditions from Celiac Disease.
Serology tests
Small bowel series: An x-ray examination of the small intestine using barium is no longer considered to be a very useful study. It can be perfectly normal in many patients with Celiac Disease. If the small intestinal x-ray series is abnormal, it will probably demonstrate dilatation (in the absence of partial small bowel obstruction). However, this is a very non-specific finding and may suggest a number of different diseases.Esophagogastroduodenal (EGD) endoscopy: The use of endoscopy to examine the lining of the stomach and most proximal portion of the duodenum has been extensively used for the past quarter century. Though this procedure is usually employed in patients with esophageal reflux or acid peptic disease, the characteristic appearance of Celiac Disease may be observed during examination of the duodenum. When it is, a duodenal biopsy should be taken and examined under a light microscope. Unfortunately, an EGD will only visualize up to the third (or possibly fourth) portion of the duodenum. Fortunately, the abnormal appearance of the small intestinal biopsy in Celiac Disease is more obvious in the proximal than in the distal portions of the small intestine.
Capsule enteroscopy: The introduction of capsule enteroscopy has provided access to the entire small intestine. The findings seen on capsule enteroscopy are very non-specific -- they can provide suggestive evidence of Celiac Disease, but require small intestinal biopsy for diagnosis. Unfortunately, capsule enteroscopy does not permit acquisition of small intestinal biopsies.
Treatment of Celiac Disease
After
the diagnosis of Celiac Disease is established, the patient should be
placed on a gluten-free diet. The patient should be referred to a
skilled dietitian to provide education concerning the details and
pitfulls of a gluten-free diet. The patient should also receive
education about the disease with emphasis on lifelong adherence to a
gluten-free diet. A list of common gluten-containing foods is provided
in the websites shown in the Table. Most patients will notice improved
clinical symptoms within a few weeks of gluten restriction. Such
symptomatic improvement should be associated with a reduction of the tTG
antibody assay within months. Ideally, the patient’s symptoms should
disappear and tTG assay should be normal within six months or less.
Such a pattern will establish the diagnosis of Celiac Disease. In
addition, the patient should be advised that family members should
undergo serologic testing for Celiac Disease and nutritional
deficiencies should be identified and, if present, treated. What might be responsible for failure to respond to a gluten-free diet? The most likely explanation is continued intake of gluten (either inadvertently or because of a failure to follow gluten restriction). Celiac Disease support groups are present throughout the United States (and most Western European countries) and are very willing to provide assistance and support to help ensure maintenance of a gluten-free diet. (A list of these organizations is also provided in the Table.)
The other possibility that must be considered in patients with a presumptive diagnosis of Celiac Disease who do not respond to gluten withdrawal and are maintaining a gluten-free diet is that the initial diagnosis was incorrect. These patients should be reevaluated. This group will likely represent considerably less than 10% of the initially diagnosed patients, and it is quite heterogenous. Possible diagnoses include: 1) Other causes of an abnormal duodenal biopsy (see above). Such patients usually will lack positive tTG antibody assay, and so should be relatively easy to differentiate from Celiac Disease; 2) Complications of Celiac Disease such as small intestine adenocarcinoma, enteropathy-associated T-cell lymphoma, and refractory sprue; 3) Refractory sprue is also a very heterogeneous group of patients that include those with another explanation for their diarrhea and malabsorption (e.g., microscopic colitis, pancreatic insufficiency). This group, in general, does not have a very good prognosis.
The demonstration of an increased number of individuals with positive Celiac serology studies with varying degrees of clinical manifestations of Celiac Disease has led to the development of the concept of Celiac Disease as an ‘”iceberg” disease. That is, there are a very small number of patients with Celiac Disease (at the top of the iceberg pyramid) who have typical signs and symptoms of Celiac Disease, while the vast majority of patients below the waterline of this iceberg have either: 1) symptomatic disease with atypical manifestations; 2) essentially asymptomatic disease with typical small intestinal pathology consistent with Celiac Disease; or 3) positive serologies without any evidence of Celiac Disease (including examination of the small intestine by biopsy).
The top of the pyramid is active disease; the middle segment of the pyramid represents latent Celiac Disease; while the base of the pyramid are those without symptoms or signs who have positive serologies, denoted as having silent Celiac Disease.
Conclusion
Celiac Disease is a fascinating entity with protean manifestations. It affects many more individuals than previously thought,. with a much greater spectrum of symptoms than originally suspected. There is great hope for new diagnostic and therapeutic approaches to this disease in the next decade. Innovative approaches to treatment presently underdevelopment include: 1) specific enzymes that could detoxify gluten-containing foods making them suitable for eating and 2) compounds that could modify the spaces (tight junctions) between intestinal cells to reduce the possibility that gluten-derived protein could initiate an autoimmune response. Certainly there has been much greater interest in this medical problem in the past decade with the expectation that further research in the future will bring increased understanding and improved medical care.Web Sites With Good Information About Celiac Disease
WEB SITES for NATIONAL CELIAC ORGANIZATIONS:
Celiac/Sprue Assn. Omaha, NE www.csaceliacs.org
Celiac Disease Foundation, Studio City, CA www.celiac.org
Gluten Intolerance Group www.gluten.net
Celiac Disease Research Center www.celiacsprue.org
National Celiac Disease Awareness Campaign http://celiaccentral.org
GLUTEN-FREE FOOD LISTINGS AND INFO ON THE GLUTEN-FREE DIET:
CSA/USA Commercial Products Listing www.csaceliacs.org
Clan Thompson Web site www.clanthompson.com
Delphi Forums Gluten-Free Food list
Scott’s Celiac Page www.celiac.com
Celiac Today www.celiactoday.com
GLUTEN-FREE PHARMACEUTICAL INFORMATION:
Gluten-Free Drug List www.glutenfreedrugs.com
Clan Thompson (pocket guides) www.clanthompson.com
Scott’s Celiac Page (downloadable drug lists) www.celiac.com
GLUTEN-FREE RESTAURANT AND TRAVEL WEB SITES:
(*These sites have the ability for you to put in your zip code and find restaurants in your area)
*Gluten-Free on the go www.gluten-freeonthego.com *Gluten-Free Passport www.gluten-freepassport.com
*GIG Gluten Free Restaurant Awareness Program
*Celiac Travel www.celiac.travel.com
Bob & Ruth’s Dining and Travel Club www.bobandruths.com
Clan Thompson (Restaurant guides) www.clanthompson.com
References
Trier, JS. Diagnosis of Celiac Sprue. Gastroenterology 115:211-21 , 1998
Fasano, A, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a large multi-center study. Arch Intern Med 163:286-292, 2003.
NIH Consensus Development Conference on Celiac Disease. Gastroenterology 128: S1-S140, 2005.
Green, P, Cellier, C. Celiac Disease. New Engl J Med 357:1731-1743, 2007