10 Dermatologic Signs of Celiac Disease - Dermatology Advisor

10 Dermatologic Signs of Celiac Disease

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  • Dermatitis herpetiformis (DH) is the best characterized and most common cutaneous manifestation of CD.2,3 Genetic studies have shown both CD and DH to be strongly associated with human leukocyte antigen (HLA)-DQ2 and HLA-DQ8, with 86% of all patients with CD and DH being positive for HLA-DQ2 and most of the remainder being positive for HLA-DQ8.4 Patients typically have symmetrically distributed itchy papules and vesicles on their elbows, knees, and buttocks, but the upper back, abdomen, scalp, and face can also be affected.3 Rarely, oral lesions and/or purpuric lesions on the hands and feet may be observed. Overt GI symptoms are uncommon, despite 75% of patients with DH having distorted villous architecture.3 A gluten-free diet is the gold-standard treatment, regardless of whether there is villous atrophy. Patients who follow a strict gluten-free diet have an excellent long-term prognosis, with an overall mortality rate lower than that of the general population.3

    Dermatitis Herpetiformis

    Dermatitis herpetiformis (DH) is the best characterized and most common cutaneous manifestation of CD.2,3 Genetic studies have shown both CD and DH to be strongly associated with human leukocyte antigen (HLA)-DQ2 and HLA-DQ8, with 86% of all patients with CD and DH being positive for HLA-DQ2 and most of the remainder being positive for HLA-DQ8.4

    Patients typically have symmetrically distributed itchy papules and vesicles on their elbows, knees, and buttocks, but the upper back, abdomen, scalp, and face can also be affected.3 Rarely, oral lesions and/or purpuric lesions on the hands and feet may be observed. Overt GI symptoms are uncommon, despite 75% of patients with DH having distorted villous architecture.3 A gluten-free diet is the gold-standard treatment, regardless of whether there is villous atrophy. Patients who follow a strict gluten-free diet have an excellent long-term prognosis, with an overall mortality rate lower than that of the general population.3

  • Atopic dermatitis (AD) has been linked with CD in adults and children. Pediatric patients with AD have been reported to have a 4-fold greater risk for CD developing than the general pediatric population, and adults with CD have been reported to be 3-fold more likely to have AD than adults without CD.2 The exact pathogenesis of AD in patients with CD remains unclear but is likely multifactorial, involving genetic, environmental, and other factors. Patients with AD may have a variety of cutaneous findings, including erythema, lichenification, prurigo nodules, and scaling, which is accompanied by itching and pain.2 Patients may also report sleep disturbances, fatigue, and depression or anxiety. A gluten-free diet can be tried but current data have shown limited efficacy. In a cohort of patients with CD and at least one allergy, 1 year of a gluten-free diet did not change the prevalence of AD or allergies.7

    Atopic Dermatitis

    Atopic dermatitis (AD) has been linked with CD in adults and children. Pediatric patients with AD have been reported to have a 4-fold greater risk for CD developing than the general pediatric population, and adults with CD have been reported to be 3-fold more likely to have AD than adults without CD.2 The exact pathogenesis of AD in patients with CD remains unclear but is likely multifactorial, involving genetic, environmental, and other factors.

    Patients with AD may have a variety of cutaneous findings, including erythema, lichenification, prurigo nodules, and scaling, which is accompanied by itching and pain.2 Patients may also report sleep disturbances, fatigue, and depression or anxiety. A gluten-free diet can be tried but current data have shown limited efficacy. In a cohort of patients with CD and at least one allergy, 1 year of a gluten-free diet did not change the prevalence of AD or allergies.7

  • Psoriasis

    Psoriasis

    An association between psoriasis and CD has long been observed, and in 2017, a systematic review and meta-analysis of observational studies reported a 3-fold higher risk for CD among patients with psoriasis compared with individuals without psoriasis.8 The meta-analysis included nearly 13,000 patients with psoriasis and 25,000 comparators without psoriasis. Although the pathophysiologic mechanisms linking CD and psoriasis remain unclear, several hypotheses have been suggested, such as shared genes and the presence of antigliadin antibodies in both diseases.8

    Patients with psoriasis may have thick, red plaques that are covered with coarse, silvery scales, with the elbows, knees, scalp, and periumbilical and lumbar regions most commonly affected.2 A gluten-free diet has been reported to be beneficial in patients with psoriasis and biopsy-confirmed CD, as well as in patients with psoriasis who do not have CD but still test positive for antibodies to gluten.9

  • Rosacea has been reported to share genetic risk loci with CD and other autoimmune disorders.10 Several studies have shown a higher prevalence of CD among individuals with rosacea, although the correlation appears strongest in women, with one large Danish population-based control study reporting an odds ratio of 2.03 (95% CI, 1.35-3.07) in women and the association not reaching statistical significance in men.2,11 The study did not examine rosacea subtypes; thus, it is unclear whether the risk spans all subtypes. Nevertheless, based on their data, the Danish investigators suggested there may be benefit to asking patients with rosacea about their personal and family history of autoimmune diseases and potentially screening them for CD.11

    Rosacea

    Rosacea has been reported to share genetic risk loci with CD and other autoimmune disorders.10 Several studies have shown a higher prevalence of CD among individuals with rosacea, although the correlation appears strongest in women, with one large Danish population-based control study reporting an odds ratio of 2.03 (95% CI, 1.35-3.07) in women and the association not reaching statistical significance in men.2,11 The study did not examine rosacea subtypes; thus, it is unclear whether the risk spans all subtypes. Nevertheless, based on their data, the Danish investigators suggested there may be benefit to asking patients with rosacea about their personal and family history of autoimmune diseases and potentially screening them for CD.11

  • The association between alopecia areata (AA) and CD remains unclear. Some reports have shown an association, but the overall prevalence in people with CD appears similar to that of the general population, ranging from 1 in 85 to 1 in 116 persons.2 However, in children with AA, the association may be stronger. In a small Turkish study of 12 children with AA, 5 (41.7%) were found to have CD.12 None of these children had gastrointestinal symptoms. Once a gluten-free diet was administered, all 5 children experienced complete hair regrowth. 12 This finding is consistent with other literature reporting AA to improve or resolve following a gluten-free diet, an effect that has been attributed to the diet normalizing the immune response.2 Subsequently, CD should be considered and screened for in individuals with unexplained AA, particularly children.2,12

    Alopecia Areata

    The association between alopecia areata (AA) and CD remains unclear. Some reports have shown an association, but the overall prevalence in people with CD appears similar to that of the general population, ranging from 1 in 85 to 1 in 116 persons.2 However, in children with AA, the association may be stronger. In a small Turkish study of 12 children with AA, 5 (41.7%) were found to have CD.12 None of these children had gastrointestinal symptoms. Once a gluten-free diet was administered, all 5 children experienced complete hair regrowth. 12 This finding is consistent with other literature reporting AA to improve or resolve following a gluten-free diet, an effect that has been attributed to the diet normalizing the immune response.2 Subsequently, CD should be considered and screened for in individuals with unexplained AA, particularly children.2,12

  • Since the 1970s, there have been sporadic reports associating cutaneous vasculitis (CV) with CD.2 It has been suggested that CV in these patients might occur secondary to exogenous or endogenous antigens permeating the small bowel mucosa, which is more permeable as a result of villous atrophy, resulting in the formation of circulating immune complexes that get deposited into the skin and other tissue.13 In 1981, Meyers and colleagues reported a case of CV in a patient with uncontrolled CD whose CV resolved following a strict gluten-free diet.13 Although CV appears to be a rare complication of CD, its presence should prompt suspicion of CD. Patients may have palpable purpura, petechiae, urticaria, ulcers, livedo reticularis, and nodules, most commonly affecting the lower extremities.2 Ideally, a skin biopsy should be undertaken within 48 hours of lesion onset to confirm a CV diagnosis.2

    Cutaneous Vasculitis

    Since the 1970s, there have been sporadic reports associating cutaneous vasculitis (CV) with CD.2 It has been suggested that CV in these patients might occur secondary to exogenous or endogenous antigens permeating the small bowel mucosa, which is more permeable as a result of villous atrophy, resulting in the formation of circulating immune complexes that get deposited into the skin and other tissue.13 In 1981, Meyers and colleagues reported a case of CV in a patient with uncontrolled CD whose CV resolved following a strict gluten-free diet.13

    Although CV appears to be a rare complication of CD, its presence should prompt suspicion of CD. Patients may have palpable purpura, petechiae, urticaria, ulcers, livedo reticularis, and nodules, most commonly affecting the lower extremities.2 Ideally, a skin biopsy should be undertaken within 48 hours of lesion onset to confirm a CV diagnosis.2

  • Many other skin conditions have been associated with CD, including dermatomyositis and vitiligo, both of which have been reported to improve following a gluten-free diet.2 Less frequent associations have been reported with conditions such as lichen planus, linear immunoglobulin A bullous dermatosi, necrolytic migratory erythema, generalized acquired cutis laxa, and atypical mole syndrome, and the effect of a gluten-free diet on these cutaneous disorders remains unclear.2 An increased risk for cutaneous malignant melanoma has also been suggested in patients with CD, with one study reporting a 5-fold increased risk.14 However, a more recent Swedish study including >29,000 patients with CD found no such association.15 In the study, only 0.3% of patients with CD developed cutaneous malignant melanoma. Because CD is associated with so many skin conditions, it should be considered in the differential diagnosis of any patient with cutaneous abnormalities, particularly when the cause is unclear.2

    Other Skin Conditions

    Many other skin conditions have been associated with CD, including dermatomyositis and vitiligo, both of which have been reported to improve following a gluten-free diet.2 Less frequent associations have been reported with conditions such as lichen planus, linear immunoglobulin A bullous dermatosi, necrolytic migratory erythema, generalized acquired cutis laxa, and atypical mole syndrome, and the effect of a gluten-free diet on these cutaneous disorders remains unclear.2 An increased risk for cutaneous malignant melanoma has also been suggested in patients with CD, with one study reporting a 5-fold increased risk.14 However, a more recent Swedish study including >29,000 patients with CD found no such association.15 In the study, only 0.3% of patients with CD developed cutaneous malignant melanoma. Because CD is associated with so many skin conditions, it should be considered in the differential diagnosis of any patient with cutaneous abnormalities, particularly when the cause is unclear.2

  • Recurrent aphthous stomatitis (RAS) is one of the most well-documented oral manifestations of CD and may be the only symptom of CD; thus, CD should be considered in the differential diagnosis of patients with RAS.16 In a Canadian survey-based study that included nearly 3000 respondents with biopsy-proven CD, 16% of children (<16 years) and 26% of adults reported RAS.16,17 Although the exact cause of RAS in patients with CD is unknown, it has been suspected that CD-related malabsorption may result in a hematinic deficiency (ie, iron, folic acid, vitamins B6 and B12), which has been associated with RAS in non-CD studies.2,16,18 Patients with RAS may have one or more round- or oval-shaped, shallow, punched-out-appearing, painful oral ulcers.19 The pain usually lasts 3 to 4 days and the ulcers usually resolve in 7 to 14 days. RAS may recur at intervals of every few days to every few months.19

    Aphthous Stomatitis

    Recurrent aphthous stomatitis (RAS) is one of the most well-documented oral manifestations of CD and may be the only symptom of CD; thus, CD should be considered in the differential diagnosis of patients with RAS.16 In a Canadian survey-based study that included nearly 3000 respondents with biopsy-proven CD, 16% of children (<16 years) and 26% of adults reported RAS.16,17 Although the exact cause of RAS in patients with CD is unknown, it has been suspected that CD-related malabsorption may result in a hematinic deficiency (ie, iron, folic acid, vitamins B6 and B12), which has been associated with RAS in non-CD studies.2,16,18

    Patients with RAS may have one or more round- or oval-shaped, shallow, punched-out-appearing, painful oral ulcers.19 The pain usually lasts 3 to 4 days and the ulcers usually resolve in 7 to 14 days. RAS may recur at intervals of every few days to every few months.19

  • In addition to RAS, a variety of other oral cavity disorders have been associated with CD, including dental enamel defects, delayed eruption, cheilosis, oral lichen planus, and atrophic glossitis.16 Among these, dental enamel defects are the most widely recognized. In 1990, Aine and colleagues developed a grading system to classify dental enamel defects in patients with CD.20 Grade I defects include discolored enamel; grade II defects include rough enamel surfaces with horizontal grooves and shallow pits; grade III defects include deep horizontal grooves and large vertical pits; and grade IV defects include structural defects severe enough to alter the shape of the tooth.16,20 Patients observed to have oral cavity defects should be asked about other symptoms and family history, and serologic screening tests should be considered when warranted to ensure a timely CD diagnosis.16,20

    Other Oral Cavity Disorders

    In addition to RAS, a variety of other oral cavity disorders have been associated with CD, including dental enamel defects, delayed eruption, cheilosis, oral lichen planus, and atrophic glossitis.16 Among these, dental enamel defects are the most widely recognized. In 1990, Aine and colleagues developed a grading system to classify dental enamel defects in patients with CD.20 Grade I defects include discolored enamel; grade II defects include rough enamel surfaces with horizontal grooves and shallow pits; grade III defects include deep horizontal grooves and large vertical pits; and grade IV defects include structural defects severe enough to alter the shape of the tooth.16,20 Patients observed to have oral cavity defects should be asked about other symptoms and family history, and serologic screening tests should be considered when warranted to ensure a timely CD diagnosis.16,20

  • The relationship between urticaria and CD remains unclear, but urticaria has been associated with the CD gene HLA-DQ8.2 Additionally, several case reports and smaller case-control studies have reported an association between urticaria and CD, and in 2013, a large population-based cohort study provided further evidence of an association, particularly with chronic urticaria (CU; duration ≥6 weeks).2,5 Among 28,900 patients with biopsy-verified CD, 453 with no previous diagnosis of urticaria were diagnosed with urticaria (expected, n=300) during follow-up, with 79 cases being CU (expected, n=41).5 Patients with urticaria have rapid onset of wheals and/or angioedema.5In patients with urticaria of unknown etiology, CD should be considered as part of the differential diagnosis, along with other autoimmune disorders.6 Adoption of a gluten-free diet has had variable success in patients with urticaria but has been reported to resolve skin flares in patients with confirmed CD-associated CU.2,6

    Urticaria

    The relationship between urticaria and CD remains unclear, but urticaria has been associated with the CD gene HLA-DQ8.2 Additionally, several case reports and smaller case-control studies have reported an association between urticaria and CD, and in 2013, a large population-based cohort study provided further evidence of an association, particularly with chronic urticaria (CU; duration ≥6 weeks).2,5 Among 28,900 patients with biopsy-verified CD, 453 with no previous diagnosis of urticaria were diagnosed with urticaria (expected, n=300) during follow-up, with 79 cases being CU (expected, n=41).5

    Patients with urticaria have rapid onset of wheals and/or angioedema.5In patients with urticaria of unknown etiology, CD should be considered as part of the differential diagnosis, along with other autoimmune disorders.6 Adoption of a gluten-free diet has had variable success in patients with urticaria but has been reported to resolve skin flares in patients with confirmed CD-associated CU.2,6

Celiac disease (CD) is an autoimmune disorder that is triggered in genetically predisposed individuals after consumption of gluten, a protein found in wheat, barley, rye, and other grains. In these individuals, gluten exposure results in an immune response that damages the lining of the small intestine (ie, intestinal villus), preventing absorption of nutrients. Although CD is most commonly recognized to cause gastrointestinal (GI) symptoms related to malabsorption, such as diarrhea, steatorrhea, and weight loss, many patients with CD do not have GI symptoms. Subsequently, the World Gastroenterology Organization has divided CD into 2 types: classical CD, which manifests with symptoms of malabsorption and non-classical CD, which may produce only mild/nonspecific or no GI symptoms but may have many extra-intestinal manifestations, including a variety of cutaneous and mucosal disorders.1

Subsequently, it has been suggested that the presence of certain skin and mucosal conditions should raise suspicion of CD, particularly when their cause remains unclear.1,2 In patients with CD-associated skin and mucosal disorders, a gluten-free diet often resolves symptoms and reduces the risks associated with untreated CD, such as osteoporosis, depression, and an increased risk for lymphomas and bowel cancer.1,2

Slideshow compiled by Christina Loguidice

References

1. World Gastroenterology Organisation. Celiac disease. http://www.worldgastroenterology.org/guidelines/global-guidelines/celiac-disease/celiac-disease-english. Published July 2016. Accessed December 28, 2018.   

2. Rodrigo L, Beteta-Gorriti V, Alvarez N, et al. Cutaneous and mucosal manifestations associated with celiac disease. Nutrients. 2018;10(7):800.

3. Reunala T, Salmi TT, Hervonen K, Kaukinen K, Collin P. Dermatitis herpetiformis: a common extraintestinal manifestation of coeliac disease. Nutrients. 2018;10(5):602.

4. Marietta E, Black K, Camilleri M, et al. A new model for dermatitis herpetiformis that uses HLA-DQ8 transgenic NOD mice. J Clin Invest. 2004;114(8):1090-1097.

5. Ludvigsson JF, Lindelöf B, Rashtak S, Rubio-Tapia A, Murray JA. Does urticaria risk increase in patients with celiac disease? A large population-based cohort studyEur J Dermatol. 2013;23(5):681-687.

6. Haussmann J, Sekar A. Chronic urticaria: a cutaneous manifestation of celiac disease. Can J Gastroenterol. 2006;20(4):291-293.

7. Ciacci C, Cavallaro R, Iovino P, et al. Allergy prevalence in adult celiac disease. J Allergy Clin Immunol. 2004;113(6):1199-1203.

8. Ungprasert P, Wijarnpreecha K, Kittanamongkolchai W. Psoriasis and risk of celiac disease: a systematic review and meta-analysis. Indian J Dermatol. 2017;62(1):41-46.

9. National Psoriasis Foundation. Do gluten-free diets improve psoriasis? Published September 10, 2015. Accessed December 28, 2018.

10. Chang ALS, Raber I, Xu J, et al. Assessment of the genetic basis of rosacea by genome-wide association study. J Invest Dermatol. 2015;135(6):1548-1555.

11. Egeberg A, Hansen PR, Gislason GH, Thyssen JP. Clustering of autoimmune diseases in patients with rosacea. J Am Acad Dermatol. 2016;74(4):667-672.

12. Ertekin V, Tosun MS, Erdem T. Screening of celiac disease in children with alopecia areata. Indian J Dermatol. 2014;59(3):317.

13. Meyers S, Dikman S, Spiera H, Schultz N, Janowitz HD. Cutaneous vasculitis complicating coeliac disease. Gut. 1981;22(1):61-64.

14. Green PH, Fleischauer AT, Bhagat G, Goyal R, Jabri B, Neugut AI. Risk of malignancy in patients with celiac disease. Am J Med. 2003;115(3):191-195.

15. Lebwohl B, Eriksson H, Hansson J, Green PH, Ludvigsson JF. Risk of cutaneous malignant melanoma in patients with celiac disease: a population-based study. J Am Acad Dermatol. 2014;71(2):245-248.

16. Rashid M, Zarkadas M, Anca A, Limeback H. Oral manifestations of celiac disease: a clinical guide for dentists. J Can Dent Assoc. 2011;77:b39.

17. Cranney A, Zarkadas M, Graham ID, et al. The Canadian celiac health survey. Dig Dis Sci. 2007;52(4):1087-1095.

18. Sun A, Chen HM, Cheng SJ, et al. Significant association of deficiencies of hemoglobin, iron, vitamin B12, and folic acid and high homocysteine level with recurrent aphthous stomatitis. J Oral Pathol Med. 2015;44(4):300-305.

19. Mirowski G. Aphthous Stomatitis Clinical Presentation. Medscape. Updated May 14, 2018. Accessed January 3, 2019.

20. Aine L, Mäki M, Collin P, Keyriläinen O. Dental enamel defects in celiac disease. J Oral Pathol Med. 1990;19(6):241-245.

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