C. Robert Dahl, M.D.
Gastroenterologist, Wheat Ridge, Colorado
Member of the CSA Medical Advisory Board
Presentation at the 23rd Annual CSA Conference
Celiac disease (CD) is one of the great mimics in gastroenterology in particular and medicine in general. Of 100 patients with CD, just over 10 percent present with classical overt symptoms of malabsorption such as weight loss, diarrhea and nutritional deficiencies. About 10 percent are incorrectly diagnosed for some length of time, in some cases years. Forty percent present in an atypical manner, which leads to lengthy delay in diagnosis. About 33 percent of patients have clinically silent disease and 7 percent have latent CD (no symptoms or small bowel lesion but will develop CD later, or had disease at an early age and resolved).
Better awareness of "non-classical" disease and improved screening tests suggest that the prevalence of celiac disease is underestimated in most populations. It is surprisingly common (one of 250 people in the United States are positive for celiac disease antibody), where overt disease in the U.S. is uncommon. In 1,000 consecutive patients in the United Kingdom with symptoms of irritable bowel syndrome, anemia, chronic diarrhea, fatigue, thyroid disease, diabetes, weight loss, short stature, epilepsy, infertility, arthralgia and eczema, 30 of the 1,000 had biopsy-confirmed celiac disease. Most (25 of 30) had little to no gastrointestinal symptoms. The most common abnormality in these patients was anemia with symptoms related to anemia.
Celiac disease may present in a variety of different ways: recurring abdominal pain and bloating, chronic diarrhea, constipation (in a few patients), excessive rectal gas, weight loss, mouth sores, fatigue, anemia (iron deficiency), osteopenia (osteomalacia, osteoporosis), swelling, fluid in the abdomen, behavior changes, mood disorders, growth retardation or with few or no apparent symptoms at all.
Celiac disease is associated with a wide range of autoimmune (attack by one's immune system against oneself) diseases including insulin-dependent diabetes, dermatitis herpetiformis, autoimmune thyroid disease, autoimmune hepatitis, primary biliary cirrhosis, atrophic gastritis, gluten-related ataxia and connective tissue diseases. This has been explained by the sharing of certain common genetic factors. It has been recently discovered that the prevalence of autoimmune disorders in celiac disease is related to the duration of exposure to gluten.
The longer the exposure to gluten, the greater the risk of autoimmunity developing in other organ systems. Also, it is apparent that those who had been challenged with gluten for diagnostic purposes had an increased risk for developing autoimmune disorders. These data add weight to the argument for the development of screening programs to ensure diagnosis as early as possible. It also casts doubt on the practice of gluten challenge to confirm the diagnosis of CD.
Celiac disease has a strong association with insulin dependent diabetes. The estimated prevalence of celiac disease was found to be 6 to 8 percent in these diabetics, suggesting that screening is justified in patients with newly diagnosed insulin-dependent diabetes. Finding and treating these diabetics with CD dramatically improves insulin therapy in these often brittle patients.
Neurological abnormalities were formerly thought to be sequel to the gut disease, but it is now recognized that they may not only precede celiac disease but can also be its only manifestation. It is thought that in celiac disease the target organ for gluten sensitivity is the cerebellum or peripheral nerves, a situation analogous to that of the skin in dermatitis herpetiformis. Patients with gluten-related ataxia had antigliadin IgG or IgA antibodies. These patients had HLA genotypes known to be associated with gluten-sensitive enteropathy. Duodenal biopsies showed changes compatible with celiac disease in less than 50 percent of patients, and 60 percent had no GI symptoms. Antigliadin antibody testing is essential in the assessment of idiopathic ataxias. Endomysial antibodies are not as reliable because they may be positive only in those with gut involvement, missing those without the small bowel lesion. Both the ataxia and the neuropathy in these patients may be reversible with adherence to a gluten-free diet.
Celiac disease is strongly associated with osteomalacia and osteoporosis. Studies have suggested that treatment of malabsorption with a gluten-free diet reverses the loss of calcium in those with osteomalacia. However, recently there has been data to suggest that reduction in bone mass in those with osteoporosis is related to the presence of secondary hyperparathyroidism, probably caused by vitamin D deficiency. Therefore, a gluten-free diet, calcium and vitamin D are all important to reverse osteoporosis in these patients.
In untreated mothers, there is an increased risk of low birth weight and intrauterine growth retardation. This indicates that treatment of celiac disease may be important in the prevention of fetal growth retardation and may have implications regarding screening.
In patients with untreated CD, there is an increased risk of cancer. Lymphoma of the GI tract is increased 30 times in these people. There is a three-fold increase in intestinal adenocarcinoma, an eight-fold increase in esophageal cancer and a three-fold increase of all types of cancer. This association of cancer with untreated CD again emphasizes the importance of early diagnosis.
The diagnosis of CD is often delayed. In the U.S. , the delay may be as long as 10 years or more in some patients. CD is often confused with a long list of disorders and continues to be under-diagnosed. With the advent of better serological testing with endomysial antibodies, the diagnosis of celiac disease has been much easier to establish.
Detecting antibodies to tissue transglutaminase (tTG), the enzyme identified as the autoantigen of endomysial antibodies, has been recently reported. The ELISA and radioligand assay for IgAtTG and IgG-tTG have both a high specificity and sensitivity of near 99 percent, avoid the need for animal material and have less inter-observer variation than the endomyseal antibody determination. The confirming study is small bowel biopsy of the distal duodenum with the upper endoscope. Though not specific, the pathology shows blunted villi, elongated crypts and chronic inflammatory infiltration which is consistent with celiac sprue. The diagnosis is established by a clinical response to a gluten-free diet.
he underlying pathogenesis is related to genetic factors, which are currently being clarified. Gliadin (gluten) found in wheat, barley, rye and to a lesser extent oats drives the immune response in the genetically predisposed gut that results in the chronic inflammation of the small bowel. In some cases, there is a related biological agent (virus or bacteria). Recently there has been data to suggest that early-life gliadin exposure may play a role in the degree of intolerance to gliadin that is manifest in the genetically predisposed infant.
The treatment is as close to an absolute gluten-free diet that can be achieved for life. Other important treatment of CD is initial avoidance of dairy products (secondary lactose intolerance) and replacement of nutritional deficiencies.
Clinical improvement occurs in 70 percent of patients within two weeks. Some will take longer but most will significantly improve within six weeks. Histological changes may take up to two years in some adults. Even then there may not be a return to absolute normal, although the patient is normal clinically. IgA anti-tTG become negative in four to six weeks. The risk of malignancy approaches baseline after five years on a strict gluten-free diet.
The diagnosis should be reconsidered if there is no clinical improvement after three to six months. Those individuals who do not respond to a gluten-free diet, or who relapse with significant improvement in the intestinal inflammation (on repeat biopsy), have an additional disorder to explain the ongoing symptoms. Those patients with persistent small intestinal inflammation and injury are usually inadvertently ingesting gliadin or have evidence of "refractory sprue."
The recognition that there is a high prevalence of undiagnosed silent celiac disease in Western populations is already leading some experts to call for universal screening. Increasing evidence of the adverse consequences relating to diagnostic delay and easier screening assays such as tTG make the routine screening of children aged two to five years likely to become a reality in the near future.
CSA Library Series is a collection of articles that pertain to celiac disease and dermatitis herpetiformis. Most of these articles have appeared in CSA’s quarterly newsletter, Lifeline, which all CSA members receive. Historic articles included in these resources may or may not include updated notes. Updated information indicated in red type. Articles represent the work of the author.