Who Should get Tested

How does celiac disease present? And what about other gluten-related disorders?
Celiac disease is often referred to as a “clinical chameleon” because of its varied presentations, ranging from malabsorption to fatigue to depression1. These presentations and other signs and symptoms of celiac disease can often overlap with other conditions. Some individuals may not present with any symptoms, a subset of patients that are estimated to make up as much as 38% of the diagnosed population2,3. In fact, experts assess that the majority of patients in the general population present with symptoms that are below the threshold of clinical detection4, causing them to remain undiagnosed or misdiagnosed with another condition. Lactose intolerance and irritable bowel syndrome are two common misdiagnoses5.

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Once thought to primarily affect children6 and present with only malabsorptive symptoms8, the face of modern celiac disease has changed. It is now recognized as one of the most common lifelong disorders in Europe9 and in the U.S12, with an increased prevalence of fourfold since 1950 in the U.S.13
Celiac disease can develop at any time and can be diagnosed at any age. It is important to note that, at present, celiac disease is most frequently diagnosed in the fourth to fifth decade of life8. Although celiac disease impacts both men and women, at this time it is diagnosed largely in females with recent research indicating that 60% to 70% of those diagnosed with celiac disease are women8, 9, 10. The healthcare seeking behaviors of women, and perhaps even symptoms, are thought to largely impact this difference.
The varied and sometimes nonspecific manifestations of celiac disease can make it challenging to diagnose. As a result, 95% of the 3 million Americans with celiac disease currently remain undiagnosed. Left untreated, persons with celiac disease have nearly a fourfold increased risk of death.13 Other complications include, but are not limited to, bone disease, reproductive health problems and decreased quality of life.
It is vital that primary care providers and other physicians learn about the multiple ways in which celiac disease can present and have a heightened suspicion among their patient populations2. You play a pivotal role in identifying individuals at high risk for celiac disease and performing serological testing, the first step in diagnosing celiac disease.
Celiac disease occurs in12:
  • 1 in 133 healthy people
  • 1 in 22 first-degree relatives
  • 1 in 39 second-degree relatives
Know the Symptoms
For many years, symptoms of malabsorption such as diarrhea, weight loss, steatorrhoea or growth failure were considered the primary markers of celiac disease. These signs and symptoms are known as “classical celiac disease.”14 We now know that many celiac patients do not experience symptoms of malabsorption at all, but instead present with extra-intestinal symptoms or non-classical symptoms14,15. Still yet, others may not present with clinically evident symptoms of celiac disease, thereby falling below the threshold of clinical detection (as mentioned above). These patients can be classified as having “subclinical celiac disease”14. Some of these patients may not even see a difference upon starting a gluten-free diet, although it is still necessary that they strictly follow it. The journey to diagnosis in individuals with subclinical celiac disease is often started when lab results indicative of celiac disease are seen, such as iron deficiency anemia, osteoporosis and abnormal liver function tests. Fatigue is commonly experienced, although it is difficult for patients to detect as abnormal.14 These patients often do notice a substantial increase in energy after initiating a gluten-free diet.
As outlined in a recent publication authored by a team of 16 expert physicians14, clinical presentations of celiac disease can be classified as follows: 
  • Classical celiac disease presents with signs and symptoms of malabsorption. Diarrhea, steatorrhoea, weight loss or growth failure is required.1
  • Non-classical celiac disease presents without signs or symptoms of malabsoprtion.
  • Subclinical celiac disease presents with symptoms that typically fall below the average threshold of clinical detection.At times you may have heard terminology used to describe such symptoms as “silent celiac disease” or “asymptomatic.” These terms are now discouraged, and “subclinical celiac disease” is the preferred nomenclature.
  • Symptomatic celiac disease is a term used to describe gastrointestinal and/or extraintestinal symptoms attributable to gluten ingestion that are evident to physicians when presented during clinical practice.
  • Potential celiac disease is not identifiable by symptoms alone. It relates to patients who have a normal histology but have a positive celiac disease serology. As a result of this positive serology, persons with potential celiac disease are at an increased risk for developing celiac disease. At times you may have heard this patient population called “latent celiac disease.” This particular term is now discouraged, and “potential celiac disease” is the preferred terminology.
In addition to patients presenting with signs of malabsorption or little to no symptoms at all (as described above), common clinical presentations include:
  • Unexplained iron deficiency anemia
  • Fatigue
  • Depression
  • Ataxia
  • Constipation
  • Abdominal pain or bloating
  • Dermatitis herpetiformis
  • Alopecia
  • Aphthous stomatitis
  • Recurrent miscarriages or unexplained infertility
  • Delayed puberty
  • Osteopenia and osteoporosis
  • Dental enamel defects
  • Vitamin or mineral deficiencies (Common deficiencies include: iron, calcium, vitamin D,   zinc, vitamin B12)
Identify At-Risk Populations
Patients with celiac disease have a greater likelihood of experiencing other conditions and testing is recommended in many.16
It is recommended to test for celiac disease in patients with classical or symptomatic signs of celiac disease who also present with the following: autoimmune hepatitis; Down syndrome; premature onset osteoporosis; primary biliary cirrhosis; unexplained elevations in liver transaminase levels; and unexplained iron deficiency anemia. 
Testing is also recommended when any of the following conditions are present: 1st or 2nd degree relative with celiac disease; autoimmune thyroid disease; peripheral neuropathy; cerebellar ataxia; irritable bowel syndrome; selective IgA deficiency; Type 1 diabetes; and Sjögren’s and Turner syndromes.
How does non-celiac gluten sensitivity apply here?
Non-celiac gluten sensitivity is a condition that is different from celiac disease, despite the significant overlap in clinical presentations14,15, 17.
The research on non-celiac gluten sensitivity is only just beginning, but physicians estimate that up to 6% of the population, or 18 million Americans, are affected15. Non-celiac gluten sensitivity is thought to affect primarily adults15, 17. Early research suggests that non-celiac gluten sensitivity is the result of an activated innate immune response. It is not thought to be genetic.17
Within hours to days after gluten ingestion, patients develop symptoms, which can be can be both intestinal and extra-intestinal. In order of prevalence, clinical presentations observed in early research include 15,17:
  • abdominal pain
  • eczema and/or rash
  • headache
  • foggy mind
  • fatigue diarrhea
  • depression 
  • anemia
  • numbness in the legs, arms or fingers
  • joint pain 
Despite the overlapping symptoms with celiac disease, patients with non-celiac gluten sensitivity do not test positive for celiac disease based on blood testing, nor do they have the same type of intestinal histology found in individuals with celiac disease. In order to diagnose non-celiac gluten sensitivity, celiac disease must first be ruled out. In addition, other recent research suggests that wheat allergy must be excluded along with celiac disease before non-celiac gluten sensitivity can be diagnosed due to further overlapping symptoms. 14, 15, 17
How does wheat allergy fit into the gluten-related disorder spectrum?
Some researchsuggests that wheat allergy is included in the gluten-related disorders spectrum, and that in order for non-celiac gluten sensitivity to be diagnosed, wheat allergy must be excluded along with celiac disease15, 17. As such, it can be recommended that healthcare providers be prudent when suspicious of the gluten-related disorder non-celiac gluten sensitivity (see below for a full definition and further information) and consider wheat allergy as a possibility.
Wheat allergy includes a spectrum of IgE mediated immune responses involving histamine that occurs within minutes to hours after wheat exposure. Along the spectrum, classic food allergy, wheat-dependent exercise-induced anaphylaxis (WDEIA) and wheat dependent aspirin-induced anaphylaxis (WDAIA) are included. It has become evident that in some individuals, particularly with WDEIA, protein components in rye and barley can cross react with gluten, thereby indicating the need to avoid gluten and not just wheat 15, 18 For a detailed description of allergy symptoms, including wheat allergy, visit the at-risk checklist for ImmunoCAP

What is dermatitis herpetiformis and how can I recognize it?
Known as the cutaneous form of celiac disease, it presents initially as erythematous macule, ultimately developing into an urticarial papule. Granular deposition of IgA autoantibodies to transglutaminase and frequently to epidermal transglutaminase14, 19 appear in the tips of the dermal papillae and the basement membranes19. Scratching the vesicles may cause excoriations, making it visually difficult to distinguish between another similar appearing rash19.
  • Burning, itchy rash appears:
    • Symmetrically on the extensor areas of lower and upper extremities and buttocks in the vast majority
    • Trunk, scalp, face and neck may also be affected
  • Symptoms appear similar on darker skin
What is gluten ataxia and how can I recognize it?
Gluten ataxia is also known as idiopathic sporadic ataxia and positive antigliadin (AGA) - IgA or IgG antibodies in the presence or absence of enteropathy14. Research indicates that cross reactivity between gluten and Purkinje cells exists resulting in transglutaminase antibody deposition, particularly found frequently in the cerebellum, medulla and pons15.
  • Cerebellar ataxia affecting gait and frequently the limbs
  • Ocular abnormalities, such as gaze-evolked nystagmus present in majority
  • One-third have enteropathy with less displaying gastrointestinal symptoms
  • Myoclonus, palatal tremor or opsoclonus myoclonus rarely presents in conjunction with ataxia
Continue here to learn more about the diagnostic processes of gluten-related disorders. 
Additionally, further information on all of the gluten-related disorders as described above can be found throughout here


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2. Rostom A, et al. Medical Position Statement on celiac disease. Gastroenterology. 2006;131:1981-2002.

3. National Institutes of Health Consensus Development Conference Statement on Celiac Disease, June 28-30, 2004. Gastroenterology. 2005;128 (4 suppl 1):S1-S9.

4. Murray,  J. (2010). Diagnosing celiac disease: Clinical diagnosis (Part 1). ACCME Accredited Continuing Medical Education Activity.

5. Kelly, C.P. (2010). Chapter 3: Common and Uncommon Presentations of Celiac Disease. In M. Dennis & D. Leffler. Real Life with Celiac Disease: Troubleshooting and Thriving Gluten Free. (p. 21). Bethesda, MD: AGA Press.

6 Catassi C, Fabriani E: The spectrum of celiac disease in children. Baillieres Clin.
Gastroenterol. 11(3), 485–507 (1997).

7. Rampertab SD, Pooran N, Brar P et al.: Trends in the presentation of celiac disease. Am. J. Med. 119(4), 355 E.9–14 (2006).

8. Shah, S. & Leffler, D. (2010). Celiac disease: An underappreciated issue in women’s health. Womens Health (Lond Engl), 6(5): 753–766.

9. Green PHR, Stavropoulos SN, Panagi SG et al.: Characteristics of adult celiac disese in the USA: results of a national survey. Am. J. Gastroenterol. 96(1), 126–131 (2001).

10. Leffler D, Kelly CP: Celiac Disease: What The Last Few Years Have Taught us. Advances in Digestive Disease. Howden CW (Ed.) AGA Institute Press, (2007).

11. Catassi C, Fabiani E, Ratsch IM, et al. The coeliac iceberg in Italy: A multicentre antigliadin antibodies screening for coeliac disease in school-age subjects. Acta Paediatr Suppl 1996;412:29-35.

12. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease
in at-risk and not-at-risk groups in the United States: a large multicenter
study. Arch Intern Med 2003;163:286-92

13. Rubio-Tapia, A., Kyle, R.A., Kaplan, E.L., Johnson, D.R., Page, W., Erdtmann, F., et al. (1999). Increased prevalence and mortality in undiagnosed celiac disease. Gastroenterology, 137(1), 88-93.

14. Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PH, Hadjivassiliou M, Kaukinen K, Kelly CP, Leonard JN, Lundin KE, Murray JA, Sanders DS, Walker MM, Zingone F, Ciacci C. (2012). The Oslo definitions for coeliac disease and related terms. Gut, Feb 16. [Epub ahead of print]

15. Sapone, A., Bai, J.C., Ciacci, C., Dolinsek, J., Green, P.H.R., Hadjivassiliou, M., Kaukinen, K., Rostami, K., Sanders, D., Schumann, M., Ullrich, R., Villalta, D., Volta, U., Catassi, C. and Fasano, A. (2012). Spectrum of gluten-related disorders: consensus on new nomenclature and classification BMC Medicine, 10:13

16. AGA Institute Medical Position Statement on the Diagnosis and Management of Celiac Disease.
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17. Sapone, A., Lammers, K.M., Casolaro, V., Cammarota, M., Giuliano, M.T., De Rosa, M., et al. (2011). Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Medicine, 9(23).

18. Palosuo, K., Alenius, H., Varjonen, E., Kalkinnen, N. & Reunala, T. (2001). Rye y-70 and y-35 secalins and barley y-3 hordein cross-react with w-5 gliadin, a major allergen in wheat –dependent, exercise-induced anaphylaxis. Clin Exp Allergy, 31(3):466-473.

19. Bolotin, D, Petronic-Rosic. Dermatitis herpetiformis. J Am Acad   Dermatol. 2011; 64: 1017-1024.