Celiac disease is an autoimmune condition resulting from a dysregulated immunologic response to gluten in genetically susceptible individuals.1-3 This disease has changed over time with most patients currently presenting with extraintestinal symptoms of atypical celiac disease.

Nearly all cases of celiac disease (CD) occur in individuals with the major histocompatibility complex class II human leukocyte antigen (HLA) DQ2 or DQ8.1 At least one of these heterodimers is present in 30% to 40% of the general population; however, only 3% of patients with HLA-DQ2 or HLA-DQ8 develop CD, and genome-wide association studies have identified more than 100 non-HLA-related genes associated with the disease.1,4

Prevalence of Celiac Disease

Celiac disease affects up to 1% of people in Western countries, and the prevalence is on the rise.1-4 In a cohort study, Catassi et al followed 3511 patients in the US from 1974 to 1989 and found a 2-fold increase in the prevalence of CD, from 1 in every 501 persons to 1 in every 219 persons.3 The findings suggest that immunologic gluten intolerance may develop in adulthood.3 In a more recent cohort study, Catassi et al found that the prevalence of CD continued to rise in the United States, to a prevalence of 1 in 105 persons in 2001, suggesting a 5-fold increase in CD prevalence over a 30-year period.3


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Recent epidemiologic studies have shown that this relatively high prevalence extends to countries in North Africa and Asia, particularly in Iran (0.88%), Libya (0.79%), and India (0.7%).1-2

Etiology of Celiac Disease

Factors such as gluten production methods, dietary gluten levels, lifetime enteric infections, and physiologic stressors could trigger an imbalance in the immune response to gluten.3 However, the true cause of gluten intolerance is unknown, and environmental factors outside of gluten ingestion may play a role.3,4 Additional potential risk factors include shorter duration of breastfeeding, timing of initial gluten ingestion in infants, and the hygiene hypothesis; however, conflicting evidence on these risk factors is found in the literature.1,3-5

Socioeconomic factors associated with CD are not well studied, but initial research suggests that CD is less commonly diagnosed in populations with lower socioeconomic status.5 A 2015 population study conducted in the UK found that people living in areas of less socioeconomic deprivation, categorized by the Townsend index, had an 80% higher rate of CD diagnosis than those living in the most socioeconomically deprived areas.5 The cause of this discrepancy is unclear; however, it is unlikely that there is a true decreased incidence of CD in socioeconomically deprived areas.5 Rather, the data more likely reflects a lack of access to health care in medically underserved areas.5 The incidence of CD continues to rise in populations of all socioeconomic backgrounds, and primary care providers need to be aware of the often insidious and varied presentation of CD.

Symptoms of Atypical Celiac Disease

Celiac disease may present with gastrointestinal (classic) or extraintestinal (atypical or nonclassic) symptoms. Classic celiac disease has signs and symptoms similar to those of irritable bowel syndrome, presenting with diarrhea with or without signs of malabsorption, such as steatorrhea, weight loss, flatulence, abdominal pain/distention, and/or vitamin deficiencies.1,6,7 Atypical celiac disease may present as dermatitis herpetiformis, iron-deficiency anemia, idiopathic elevated transaminases, constitutional short stature, and osteopenia/osteoporosis.2,4 Other symptoms include dental enamel defects, headache, ataxia, psychiatric disorders, migraine, aphthous ulcers, stomatitis, and recurrent febrile infections with moderate neutropenia.2

A shift in initial symptoms of CD has occurred, with patients increasingly presenting with extraintestinal symptoms.1 Before 1981, diarrhea was the presenting complaint in over 90% of patients with CD, but currently it is the presenting complaint in less than 40%.8 Because extraintestinal manifestations are not recognized as classic CD symptoms, atypical presentations may go undiagnosed.2 The estimated ratio of diagnosed to undiagnosed patients with CD ranges from 1:5 to 1:8.2

Patients with undiagnosed CD are at increased risk for infertility, osteoporosis, gastrointestinal malignancy, and enteropathy-associated T-cell lymphoma.2,9 These risks are diminished with early and consistent treatment.9 The characteristic histologic changes of the disease, intestinal villi atrophy and crypt hyperplasia, typically resolve upon the elimination of gluten from a patient’s diet.9 In patients who have subclinical or potential disease, the introduction of the gluten-free diet acts as a preventive rather than a therapeutic measure.2

The age at onset of CD demonstrates a bimodal distribution.4 The first peak occurs in the first 2 years of life, shortly after weaning, when gluten is introduced; the second peak occurs in the second and third decades of life.4 Intestinal manifestations are more common during the first peak of onset, whereas extraintestinal symptoms are more common during the second peak of diagnosis.4,10 Because the average length of time from first presenting complaint to diagnosis is 10 years, primary care providers can help improve the early recognition of  nonspecific signs of atypical CD.9,11

Autoimmune disorders, particularly type 1 diabetes mellitus, autoimmune thyroid disease, Sjögren syndrome, Addison disease, and systemic lupus erythematosus, are 3 to 10 times more likely to present in patients with CD.2 Gluten-sensitivity enteropathy may present with extraintestinal symptoms, particularly in these patients.2 Evidence suggests that CD patients’ risk of developing additional autoimmune disorders increases with greater gluten exposure.2 Patient populations at high risk for CD include those with Down syndrome, type 1 diabetes, and immunoglobulin A (IgA) deficiency.4 It is important for primary care providers to understand and recognize the common manifestations and presenting symptoms of atypical CD.

Dermatitis Herpetiformis in Atypical Celiac Disease

Dermatitis herpetiformis is a skin variant of CD, and this extraintestinal presentation falls under the atypical CD umbrella.2

The mean age at diagnosis of dermatitis herpetiformis is 40 to 50 years, and early studies demonstrate a male to female ratio of 2:1.4,12 In contrast, CD demonstrates a male to female ratio of 1.5:1.4,12 The ratio of dermatitis herpetiformis to CD is 1:8 in both Finland and the United Kingdom, making it a common manifestation of atypical CD.12

The characteristic blistering lesions are burning, pleuritic, erythematous papules or vesicles that may be eroded or crusted from excoriation (Figure 1).2,10,12 The eruptions commonly are present on the buttocks and extensor surfaces of the elbows and knees, with a symmetrical distribution often in a herpetiform configuration.2,10,12 Overt gastrointestinal complaints are rare in patients with this skin condition, but duodenal biopsies demonstrate that up to 75% of patients have some degree of villous atrophy; the remaining 25% have inflammatory changes of lymphocytic enteritis.10

Figure 1. Characteristic lesions of dermatitis herpetiformis in atypical celiac disease. © Biophoto Associates / Science Source

The current hypothesis on the pathogenesis of dermatitis herpetiformis suggests that latent or active CD activates an immune complex of high avidity IgA epidermal transglutaminase (TG3) antibodies with TG3 enzymes that deposit into the papillary dermis.10,12,13 Diagnosis is based on immunofluorescence biopsy, which demonstrates deposits of IgA in the papillary dermis.2,10,12 The cornerstone of treatment is a strict gluten-free diet complemented by administration of dapsone.12,13 A gluten-free diet is essential because dapsone alone will not control CD if gluten is introduced.12 On average, dapsone may be tapered off after 2 years of a strict gluten-free diet.12

Iron-Deficiency Anemia

Iron-deficiency anemia is a common extraintestinal manifestation found in 40% of CD cases.4 Thus, anemia should raise suspicion of CD, especially as an isolated finding or in patients refractory to oral iron therapy.4,9,14,15 The pathophysiology is believed to be associated with decreased oral iron absorption due to villous atrophy and/or chronic inflammation of the duodenum.9,15 In a study of patients undergoing esophagogastroduodenoscopic assessment for iron-deficiency anemia, 15% had CD as the underlying cause.15 A meta-analysis conducted in 2018 found that approximately 1 in 31 patients with iron-deficiency anemia had biopsy-confirmed CD, resulting in a 3.2% pooled prevalence.14 A gluten-free diet is necessary to resolve enteropathy and allow absorption of oral iron.9 Oral iron supplementation may be administered in conjunction with a gluten-free diet until iron levels are restored.9

Hypertransaminasemia

Liver enzyme abnormalities often affect patients with classic and atypical CD.4,9,15,16 With atypical disease, hypertransaminasemia may be the sole presentation.16 Hypertransaminasemia is present in 40% to 50% of children and adults with classic CD at the time of presentation.4,15,16

The exact mechanisms underlying hypertransaminasemia in CD are poorly understood, but current theories indicate that increased intestinal permeability may allow antigens and inflammatory cytokines to reach the portal circulation.4,16 Patients with CD-associated hepatic injury/inflammation usually are asymptomatic, but they may present with nonspecific malaise or fatigue.16 Levels of serum aspartate aminotransferase and/or alanine aminotransferase are mildly to moderately elevated to less than 5 times the upper limit of normal.16 In addition, 66% of patients show histologic changes on liver biopsy; these changes generally are mild and nonspecific.16 Celiac disease is present in approximately 9% of patients with cryptogenic hypertransaminasemia.15,16 Therefore, serologic testing for CD should be pursued in these cases.15,16

Most patients (75% to 95%) will have a normalization of transaminase serum levels within 12 months of starting a gluten-free diet.16 Patients with nonspecific histologic changes also typically experience reversal of liver pathology with adherence to a gluten-free diet.16

Short Stature

In children, short stature may be the main presentation of atypical CD.4,9,17 Approximately 2% to 8% of children presenting with short stature without gastrointestinal complaints have underlying CD.4,9,17 Celiac disease is the most common organic cause of slow growth velocity and is even more common than growth hormone deficiency.9,18 Once endocrine abnormalities are excluded, 19% to 59% of children with short stature and no gastrointestinal complaints will be diagnosed with CD.17 The mechanisms underlying short stature in CD are unclear but may be linked to nutritional deficits.9,18 However, treatment with a gluten-free diet often leads to increased growth to target height within 2 to 3 years.9,18

Osteopenia/Osteoporosis

Celiac disease predisposes patients to decreased bone mineral density due to altered absorption of calcium and vitamin D3.4,9 Bone mineral density changes, including osteopenia and osteoporosis, affect approximately 70% of patients at the time of diagnosis.4 In a study that observed 86 consecutive patients with a new diagnosis of biopsy-confirmed CD, 40% had osteopenia and 26% had osteoporosis.9 In addition, the prevalence of CD among patients with osteoporosis is 3.4%.9,19

Osteopenia/osteoporosis may be difficult to recognize in patients with atypical CD due to the frequency of decreased bone mineralization in postmenopausal women and men of the same age, but awareness of osteopenia/osteoporosis as a potential sign of CD may minimize a delay in diagnosis in elderly patients.2

Treatment with a gluten-free diet improved bone mineral density more than expected by the standard of care.19 However, unlike pediatric patients, who are expected to fully recover bone mass following a gluten-free diet, bone mineral density may not normalize in adults who experience osteoporosis secondary to CD.9 Therefore, early identification and treatment of CD in adults is imperative to prevent this CD complication.9

Diagnosis of Celiac Disease

In patients with suspected CD, the first step to diagnosis is serologic testing.2,4,20 An antitissue transglutaminase (TG2) antibody (TG2-IgA) level is the preferred serologic test for CD and has a 90% to 98% sensitivity and 95% to 98% specificity for the disease.1,20,21 The antiendomysial antibody (EMA-IgA) test also is available, with a sensitivity of 90% to 97% and specificity of 97% to 100%.1,20 However, EMA-IgA use is limited by cost, complexity, and operator dependency, yielding variation in results.1,6,20 Detection of antigliadin antibodies is not recommended because of lower sensitivity and specificity compared with TG2-IgA and EMA-IgA autoantibodies.20,21

An IgA level also may be needed because IgA deficiency is present in up to 3% of patients with CD and a deficiency will lead to false-negative TG2-IgA and EMA-IgA results.20 In these instances, deamidated gliadin peptides (DGPIgA or DGPIgG) have excellent sensitivity and specificity of 94% and 99% for DGPIgA and 92% and 100% for DGPIgG, respectively.22

Once positive serology has been established, the gold standard of diagnosis is the duodenal biopsy.1-4,20-22 Morphologic changes vary based on patient severity but commonly show partial or complete villous atrophy, increased intraepithelial lymphocytes, increased epithelial apoptosis, and/or crypt hyperplasia.1-4,20

The American Gastroenterological Association proposed a biopsy-avoiding diagnostic pathway for celiac disease in 2019 (Figure 2).23 According to the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines from 2012, celiac disease diagnosis can be made in symptomatic children with a high TG2-IgA antibody titer (>10 times the upper limit of normal) and other positive serologic markers (eg, EMA and HLA-DQ2/DQ8) in a second blood sample without the need for duodenal biopsy.24

Figure 2. Suggested biopsy-avoiding diagnostic pathway for celiac disease from the American Gastroenterological Association. © Adapted from Husby S, et al.

Improvement in symptoms through initiation of a gluten-free diet provides further confirmation of the diagnosis. Determination of HLA-DQ2/DQ8 should be used for its negative predictive value to rule out celiac disease in selected clinical scenarios such as in patients who are seronegative with equivocal histologic findings on biopsy.23 Negative genotypes have near 100% negative predictive value for CD and are able to exclude the diagnosis.1,2,4,20

Both TG2-IgA and EMA-IgA correlate with the atrophy of intestinal villi and may produce false-negative results in patients following a gluten-free diet.1,6,20 This is an additional case in which genetic testing for HLA-DQ2/DQ8 may be performed.1,2,4,20,23 If genetic testing is positive, a gluten challenge should be initiated, with intake of at least 3 grams of gluten per day for a minimum of 2 weeks, ideally up to 8 weeks if tolerated, with repeat serology and duodenal biopsy after completion.22

Conclusion

Classic CD known for its gastrointestinal symptoms is most recognizable, but atypical CD is more common, affecting up to 50% of diagnosed cases and even more remaining undiagnosed.2 Atypical celiac disease has a wide array of presentations, including dermatitis herpetiformis, iron-deficiency anemia, idiopathic elevated transaminases, short stature, and osteopenia/osteoporosis, and may develop in patients of all ages, making diagnosis difficult.1-4 Patients who remain undiagnosed are at increased risk for long-term complications, including infertility, osteoporosis, gastrointestinal malignancy, and enteropathy-associated T-cell lymphoma.2,9 With early detection and adherence to a gluten-free diet, these risks may be diminished with resolution of symptoms.9 This places important emphasis on the primary care provider’s ability to recognize common extraintestinal presentations of atypical CD, which are often associated with nonspecific complaints.

Rachel Ziganti, MPA, PA-C, is a physician assistant working with the Department of Rheumatic and Immunologic Diseases of the Cleveland Clinic in Cleveland, Ohio; Stevie Redmond, MPA, PA-C, is director of education and associate professor in the Physician Assistant Department at Augusta University in Augusta, Georgia.

References

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