The Glutenous Gremlin: Celiac Disease

May 6, 2010 John Southrey

GLUTEN INGESTION AND CELIAC DISEASE
Celiac disease (CD) is now considered a common gastrointestinal autoimmune disease and it goes by other names such as coeliac disease, celiac sprue, non-tropical sprue, gluten intolerance, and gluten-sensitive enteropathy. It is found in people of nearly all ages throughout the world, and it can develop at any time in an at-risk individual. The most common symptom in adults is iron-deficient anemia that does not respond to iron supplementation. However, in adults, the symptoms of CD may present unexpectedly. Symptoms can vary from no gastrointestinal symptoms (silent CD) to severe malnutrition, or they can resemble an extra-intestinal (atypical) disorder. Children tend to present with the more classic signs of CD, including failure to thrive, chronic diarrhea, recurring abdominal bloating and pain, fatigue, and irritability. (1) There is no cure for CD.

CD develops after a genetically-susceptible individual ingests gluten, which causes an immune-mediated inflammatory reaction in the mucosa of the small intestine. This chronic inflammation eventually leads to the blunting or flattening of the intestinal villi (villous atrophy) and increased mucosal permeability that can interfere with normal absorption — allowing nutrients to pass through the digestive system without being absorbed. CD can lead to serious malabsorption and can affect other organ systems in the body if it remains undiagnosed and untreated. (2)

How could a harmless piece of bread be pathogenic to a person with CD? Unlike most autoimmune disorders, the environmental trigger for CD is known: it is gluten in bread, which activates an autoimmune response because it is perceived as harmful in susceptible individuals. Gluten, which gives bread its chewy texture, is a composite of storage proteins found in wheat, barley, rye and related grains within the tribe of the grass family Triticeae. Even a trace amount of gluten can trigger a response in some patients with celiac disease and have an injurious effect absent any symptoms. (3)

According to the U.S. Department of Agriculture, gluten is a ubiquitous staple in the American diet — white bread, white flour, and white rolls are among the top nine foods eaten by Americans. (4) In fact, many processed foods contain gluten and even "wheat-free" products are not necessarily gluten-free because they may contain other prohibited grains such as barley or rye. Gluten is also found in cold cuts, sandwich spreads, canned meats, salad dressings, soups, condiments, and in flavorings, seasonings, preservatives, emulsifiers, thickeners, and stabilizers. Hidden sources of gluten are common in non-food products, such as prescription and OTC drugs (as a filler or an inactive ingredient), cosmetics, and toothpaste. (4)

Permitted grains for people with CD include wild rice, corn, buckwheat, millet, amaranth, quinoa, teff, and uncontaminated oats. (5, 6)

What causes CD to become active is the subject of ongoing research, but possible triggers include surgery, pregnancy, giving birth, viral infection(s), or severe emotional stress. Researchers are also studying why it affects people differently by age and symptoms and the relationship between the degree of damage to the small intestine and the duration of the CD being undiagnosed. Some studies have found a correlation in childhood with early exposure of infants to dietary gluten: when they first started eating gluten and the amount of gluten eaten; the length of time the child was breastfed; and any early infections with enteropathic viruses. (7)

DIAGNOSING CD

CD has been called the most common and under-diagnosed autoimmune disease in the U.S., despite its apparent prevalence. (8) It presents a diagnostic challenge for physicians due to its subtle onset, wide-ranging systemic presentations, and because many patients have atypical symptoms or none at all.

Nearly all people with celiac disease manifest serologic markers (in particular the anti-transglutaminase antibody). Because of significant improvements in the sensitivity and specificity of newer antibody tests for CD (90-95%), the National Institutes of Health (NIH) recommend serologic testing as the first step in screening patients suspected for CD. Specifically, the tests look for anti-tissue transglutaminase antibodies (tTG-IgA/IgG) or endomysial antibodies (EmA-IgA/IgG). Because of limitations in specificity and sensitivity, anti-gliadin antibodies (AGA-IgA) should be interpreted with caution. In cases where the diagnosis of CD is questionable, genotyping for celiac disease is sometimes recommended since 95% of people with celiac disease carry the genes for HLA-DQ2 or HLA-DQ8. These genetic tests have a high sensitivity. (9)

If the test results are positive or if there is a high clinical suspicion of CD despite negative serology or atypical symptoms, a referral to a gastroenterologist for an intestinal biopsy — the gold standard — is recommended. (8) Once a confirmatory diagnosis is made, it is recommended that a bone mineral density test be ordered and an assessment of the patient's nutritional status be done to address any iron, folate, Vitamin D, calcium, or other deficiencies. A referral to a registered dietitian with expertise in CD is also recommended to explain and to help the patient adhere to a GF diet. (6, 10)

Despite the high sensitivity of these tests, which correlate with the degree of villous atrophy, a seronegative result does not exclude the diagnosis of CD. 2 In patients who have not undergone a diagnostic biopsy, it is important that they have been ingesting gluten (i.e., a gluten challenge) beforehand because testing while ingesting a gluten-restricted diet could result in a false negative finding. Because the villous atrophy can be patchy and variable, it is also recommended that the histology include at least four biopsy specimens interpreted by a pathologist (preferably a G.I. pathologist) to determine the degree of villous atrophy. (8)

Frustration is a common complaint among celiac patients because of these diagnostic challenges. A significant delay in CD diagnosis in patients with severe symptoms has been associated with serious complications. The fact that many cases of CD are simply not clinically evident may lead to a potentially higher risk of developing other autoimmune diseases, including an increased occurrence of CD-related intestinal malignancy and increased mortality risk (primarily from non-Hodgkin's lymphoma). (11) Therefore, obtaining an early diagnosis is imperative.

The University of Chicago Celiac Disease Center recommends testing for CD in individuals who fall under six clinical scenarios:

  1. "Children older than three and adults, regardless of symptoms, if a close relative has been diagnosed with celiac disease by biopsy. A close relative is considered to be a parent, sibling or child."
  2. "In children younger than three, with symptoms, antibody testing may not always be accurate. However, young children with symptoms (especially failure to thrive or persistent diarrhea) should be evaluated by a pediatric gastroenterologist. Children need to be eating wheat or barley based cereals for some time, up to one year before they can generate an autoimmune response to gluten and have their blood tested."
  3. "Any individual who has a related autoimmune disorder, regardless of celiac symptoms, should be tested for celiac disease, and if negative, the test should be repeated on a periodic basis. These conditions include insulin-dependent diabetes mellitus (requiring insulin therapy), Hashimoto's thyroiditis, Turner's syndrome, Williams syndrome, Graves disease, and Sjögren's disease."
  4. "Any person with Down Syndrome should be tested on a periodic basis."
  5. "Any individual who has experienced persistent miscarriage or infertility where a medical cause could not be found needs to be tested for celiac disease."

There are many other symptoms that could indicate the presence of celiac disease, including persistent gastrointestinal symptoms, bone density problems, dental enamel hypoplasia, fatigue, and neurological disorders." (1)

TREATMENT

Depending on the severity and duration of the disease, most patients with celiac disease will improve clinically and histologically if they adhere to a strict GFD. In children with CD, up to 95% may achieve mucosal recovery within 2 years or less. (12) Typically, improvement will be noted in the patient's antibody levels after approximately 6-12 months, although in adults it may take much longer for a seronegative result to be obtained. (13) Follow-up serology testing is recommended to confirm that there are no circulating antibodies arising from "hidden" gluten in the patient's diet or from the patient's non-compliance with a GFD. The most common reason for a poor clinical response is that small amounts of gluten are still being consumed. (13)

A "healed intestine" means a person now has healthy villi that can absorb nutrients from food into the bloodstream. 4 However, some authors have noted that in adult CD cases the rate of mucosal healing was uncertain. It can take several years for a full recovery — particularly in individuals with total villous atrophy at diagnosis — despite having followed a GFD and experiencing a good clinical response. Therefore, several study authors recommend systematic follow-up with intestinal biopsies in adults with CD to confirm their mucosal recovery. (4)

About 5 to 10 percent of adults with long-standing CD develop refractory celiac disease Type 1 or 2, which is a rare global malabsorption condition caused by severe injury to their intestinal lining. Refractory celiac disease is associated with a poor prognosis particularly with Type 2, considered a pre-malignant condition. Approximately 50% of patients develop enteropathy-associated T-cell lymphoma. Despite adherence to a strict GFD, these patients may not be able to absorb enough nutrients to survive, necessitating additional medical treatment and the introduction of nutrients directly into their bloodstream. (2)

AN EMERGING PUBLIC HEALTH CONCERN

In 2006, the National Institutes of Health (NIH) developed a Celiac Disease Awareness Campaign because of the low rate of diagnosis of CD in the U.S. The NIH found many Americans had never been tested because they did not feel sick or because they did not know that CD was the cause of their sickness. (14)

Recent studies have shown that about 3 million Americans or 1 in every 133 people have CD. However, many may not know they have the disease because they do not exhibit symptoms or because CD is often mistaken for other common ailments such as diarrhea, irritable bowel syndrome, fatigue, lactose intolerance, or a stress-related disorder. On average, it takes approximately 11 years for patients to receive a correct diagnosis. (15)

There is also growing evidence that undiagnosed and untreated CD is associated with a significant increase in morbidity and mortality in the U.S. In a recent 2009 Mayo Clinic study, researchers found that CD was four times more common in the U.S. than it was in the 1950s. Individuals who were unaware that they had the disease were nearly four times more likely than people without CD to have died during the 45 years of follow up. (16) The senior author of the study, Joseph Murray, MD noted that other studies have also found that for every person diagnosed with CD, there were likely 30 more who had the disease, but who went undiagnosed. (16)

SUPPORT FOR PATIENTS WITH CD

Since life-long adherence to a strict GFD is the only accepted therapeutic option for people with celiac disease, a confirmatory diagnosis of CD is undeniably a life-changing event. Indeed, adherence to such a restrictive diet in a gluten-laden world can be overwhelming particularly to a newly-diagnosed patient.

Even in a controlled environment as one's own kitchen, it requires a radically new food paradigm of maintaining separate toasters, butter sticks, jars, and cooking utensils to avoid accidental gluten contamination. For this reason, it is important for a person with CD to join a celiac support group and to develop a relationship with an experienced dietician. According to CD-experienced dieticians, the strict GF dietary mandate can lead to social isolation because a GFD, "is undoubtedly one of the most difficult diets to embrace in the U.S." (10)

In addition to dietitian-led instruction and support groups, supportive physicians, parents, siblings, friends, and spouses are crucial to successful adherence to a GFD. Particularly for adolescents — who face a monumental dietary change in their daily lives — there is evidence that with proper education and support, they will cope better with their feelings of being different and their frustration with such a restricted diet.

More information about celiac disease is available at the following web sites:

CELIAC DISEASE: MY STORY

I knew something was wrong with my physiology as I slowly hiked up the remote South Bass Trail in the Grand Canyon in late May 2008. This was my 35th hiking trip in the Canyon since 1979 and I was having significant difficulty keeping up with my wife. As we hiked up one steep switchback after another to the canyon rim to the finish of our 7-day backpacking trek, I found my legs lacking any energy and I simply had no endurance. In retrospect, the day before we left Austin to begin our trip there was a foreboding sign: I left work early because of severe abdominal pain. For nearly 15 years, I frequently suffered from abdominal bloating and pain — diagnosed and treated as IBS — despite undergoing an EGD in 2004.

Fast forward to December 2008 when I was rejected as a blood donor for the first time because my hematocrit was too low. A visit to my physician confirmed that I had iron-deficient anemia. A referral in February 2009 to my gastroenterologist led to a colonoscopy and EGD with duodenal biopsies to determine the etiology of my anemia. When the anesthesia wore off, my wife told me that the gastroenterologist found mucosal damage (scalloping) in my duodenum consistent with an autoimmune disease called celiac disease (CD).

Subsequently, the pathology report showed a severe mucosal lesion with villous blunting (consistent with malabsorption), crypt hyperplasia, increased intra-epithelial lymphocytes, epithelial injury, and increased lamina propria inflammation. Postoperative serology tests were positive for CD-related anti-tissue transglutaminase and anti-endomysium antibodies, which correlated with the mucosal damage to my small intestine.

I was then advised to maintain a strict gluten-free diet (GFD) for the rest of my life. Soon thereafter, I was also diagnosed with osteopenia secondary to my CD. According to my gastroenterologist, if I had not been so physically active, my osteopenia would have more than likely progressed to osteoporosis.

In July 2009, on a hunch, I saw an endocrinologist because I still was not feeling as well as expected, despite having eaten gluten-free (GF) for several months. The endocrinologist checked my thyroid and diagnosed me with a second autoimmune disease: Hashimoto's thyroiditis. A visit to a rheumatologist followed because of the onset of chronic symmetrical joint pain. Lab results revealed positive ANA titers and low C3 complement. So I am now being followed for periodic evaluations of my CBC, chemistry profile, and urinalysis, and an annual lupus auto-antibody panel.

Because of the hereditary nature of CD — particularly among first-degree relatives — my sister and brother and their children were also screened for CD. My sister's youngest daughter, age 16 (asymptomatic) and my brother's youngest daughter, age 15 (symptomatic) have since been diagnosed with CD.

SOURCES

  1. University of Chicago Celiac Disease Center. Symptoms. Available at http://www.celiacdisease.net/symptoms. Accessed April 29, 2010.
  2. Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology. Dec 2009, 1912-33.
  3. Rubio-Tabia A, Murray J. Celiac Disease Beyond the Gut. Clinical Gastroenterology and Hepatology. 2008; 6: 722-723.
  4. National Institutes of Health. Celiac Disease. May 2005. NIH Publication No. 05-4269. 1-8.
  5. Lowell JP. The Gluten-Free Bible. 2005
  6. Farrell RJ, Kelly C. Celiac Sprue. New England Journal of Medicine. January 17, 2002. 326(3):180-188.
  7. Gluten-Free Goes Mainstream. Arthritis Today, January-February 2010.
  8. Green PHR. Celiac disease: how many biopsies for diagnosis? Gastrointestinal Endoscopy. 2008. 67(7):1088-90.
  9. Rubio-Tapia A. Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology. July 2009. 17(1):88-93.
  10. Dennis M, Case S. Going gluten-free; a primer for clinicians. Practical Gastroenterology. April 2004. 86-104.
  11. Shamir R, Hernell O, Leshno M. Cost-effectiveness analysis of screening for celiac disease in the adult population,Medical Decision Making. May-Jun 2006. 282-293.
  12. Rubio-Tabia A, Rahim M, See J, Lahr B, Wu TT, Murray J. Mucosal recovery and mortality in adults with celiac disease after treatment with a gluten-free diet. The American Journal of Gastroenterology. 2010. 1-9.
  13. Home blood testing for celiac disease. Canadian Family Physician. February 2009. 55.
  14. National Digestive Diseases Information Clearinghouse. What I need to know about celiac disease. August 2007. NIH Publication No. 07-5755.
  15. Dennis M, Case S. Going gluten-free; a primer for clinicians. Practical Gastroenterology. April 2004. 86-104.
  16. Mayo Clinic. Mayo clinic study finds celiac disease four times more common than in the 1950s. Available at http://www.mayoclinic.org/news2009-rst/5329.html. Accessed March 16, 2010.
  17. Green PH. Mortality in celiac disease, intestinal inflammation, and gluten sensitivity. JAMA. 2009;302(11):1225-1226.
  18. Fasano A. Surprises from celiac disease. Scientific American. August 2009. 54-61.
  19. Craig DJ. Against The Grain. Columbia. Winter 2009-10. 28-33.
  20. Bolin T, Bare M, Caplan G, Daniells S. Malabsoprtion may contribute to malnutrition in the elderly. Nutrition. 2010. 1-2

About the Author

John Southrey is the Director of Cyber Consulting Services at TMLT. John can be reached at john-southrey@tmlt.org.

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