A 10-month-old boy was examined in 1965 because of weight loss, loose stools, vomiting, bloating, and iron-deficiency anemia. Fecal fat examination revealed steatorrhea. A gluten-free diet resulted in weight gain and the disappearance of the symptoms and anemia, and celiac disease was diagnosed without histological confirmation. When the boy was 2 years old, gluten consumption was resumed, but the gluten-free diet was soon reintroduced because his symptoms recurred. In the long run, however, the diet was incomplete, and a few years later he again experienced slight symptoms. Partial small bowel mucosal villous atrophy with crypt hyperplasia was detected during normal surveillance. Subsequently, the child became asymptomatic while consuming a strict gluten-free diet. In 1982 his small bowel mucosal morphology was normal, and a postpubertal gluten challenge was mounted. Eight months later, serum IgA-class antireticulin antibodies (ARA) became positive (titer 1:500) and small bowel mucosal biopsy showed total villous atrophy with crypt hyperplasia. The challenge was discontinued, and when the gluten-free diet was resumed, the antibody titers decreased. Thereafter, follow-up continued in primary health care. Thirteen years later, at the age of 31, he was readmitted to the hospital because of an itching rash on his elbows, knees, and scalp. The gluten-free diet turned out to be incomplete, and ARA was positive (titer 1:200). Skin biopsy confirmed the diagnosis of dermatitis herpetiformis, and small bowel biopsy showed partial villous atrophy with crypt hyperplasia. The rash disappeared when the patient consumed a strict gluten-free diet (Fig. 1).
A 16-year-old boy was examined in 1982 because of growth failure and delayed puberty. In addition, he had occasional abdominal pain and poor appetite and evinced aggressive behavior. ARA was positive (titer 1:200), small bowel biopsy showed subtotal villous atrophy with crypt hyperplasia, and he adopted a gluten-free diet. Regular follow-up was discontinued at the age of 18 years. Seventeen years later, at age 34, he described a bullous rash on his elbows, knees, and pubic area. The gluten-free diet was incomplete, and ARA was again positive. Small bowel biopsy showed partial villous atrophy with crypt hyperplasia, and skin biopsy showed dermatitis herpetiformis. A strict gluten-free diet alleviated the skin symptoms rapidly (Fig. 1).
We describe 3 celiac disease patients with classic abdominal symptoms and malabsorption in childhood, who subsequently experienced dermatitis herpetiformis in adulthood. These cases demonstrate that the phenotype of gluten sensitivity may change from classic enteropathy to extraintestinal disease. At the time of disease relapse in the skin, there was only partial villous atrophy in the small bowel mucosa, and no abdominal symptoms. This kind of mild enteropathy is indeed characteristic of dermatitis herpetiformis (3). There are nevertheless inflammatory changes in the mucosa (5), indicating an early stage of intestinal gluten sensitivity. Interestingly, in addition to granular IgA deposits in the skin, dermatitis herpetiformis patients may have IgA-class antitissue transglutaminase deposits in their intestinal mucosa (Fig. 2) (6). Similar deposits are also found in the mucosa of celiac patients, where they have been shown to be specific for gluten sensitivity (6). It is also noteworthy that adult patients with dermatitis herpetiformis may have dental enamel defects typical of celiac disease, the lesions having developed in childhood. Similar to our case reports, this indicates that the individuals have already been sensitive to gluten during early childhood (7). The rash in dermatitis herpetiformis responds to a strict gluten-free diet also in patients evincing only slight changes in villous architecture (8). Moreover, celiac disease and dermatitis herpetiformis share the same genetic involvement (9), further confirming that the entities are not separate disorders but belong to the same spectrum of genetic gluten intolerance (10).
In our patients, relapse of the disease came after an appreciably long asymptomatic period. Previously, the European Society for Paediatric Gastroenterology and Nutrition introduced the “2-year-rule” for the diagnosis of “transient celiac disease” (11). Transience was proved when the small intestinal mucosal architecture was normal after the patient had used a gluten-containing diet for 2 years. Although several reports have rendered this rule debatable (12,13), the concept of transient gluten intolerance is occasionally reintroduced (14–16). Simell et al (16) surveyed serum tissue transglutaminase values in children with genetic susceptibility to celiac disease and observed some negative seroconversions of antibodies without apparent reduction in gluten intake. It will be interesting to see whether these children will eventually experience celiac disease, dermatitis herpetiformis, or some other form of gluten sensitivity. In any case, our observations suggest that celiac disease is a lifelong disorder.
Untreated celiac disease carries an increased risk of serious complications such as growth retardation, anemia, osteoporosis, or lymphoma (1,2), and these may also occur in asymptomatic patients (17–19). Most of these complications can be prevented by a gluten-free diet. Our 3 patients were asymptomatic for periods despite extended gluten consumption. Without the appearance of rash they would probably have continued consuming a gluten-containing diet, which again, although we do not know, may have resulted in even more severe complications. Our findings thus support advocating a lifelong gluten-free diet after the diagnosis has been established, and discouraging unnecessary gluten challenges.
In conclusion, the phenotype of celiac disease can change from intestinal disorder to extraintestinal manifestations over time. Classic celiac disease with enteropathy and dermatitis herpetiformis both belong to the spectrum of genetic gluten sensitivity. Periodic or incomplete gluten-free diet, for instance in childhood or adolescence, may alleviate the symptoms and apparently cure gluten sensitivity, but gluten-related symptoms and even complications may occur later in life. The diet should be permanent once the diagnosis is confirmed.
1. Farrel RJ, Kelly CP. Celiac sprue. N Engl J Med 2002; 346:180–188.
2. Hill I, Dirks M, Liptak G, et al
. Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2005; 40:1–19.
3. Collin P, Reunala T. Recognition and management of the cutaneous manifestations of celiac disease. Am J Dermatol 2003; 4:13–20.
4. Collin P, Huhtala H, Virta L, et al
. Diagnosis of celiac disease in clinical practice. J Clin Gastroenterol 2007; 41:152–156.
5. Savilahti E, Reunala T, Mäki M. Increase of lymphocytes bearing the gamma/delta T cell receptor in the jejunum of patients with dermatitis herpetiformis. Gut 1992; 33:206–211.
6. Korponay-Szabo I, Halttunen T, Szalai Z, et al
. In vivo targeting of intestinal and extraintestinal transglutaminase 2 by coeliac autoantibodies. Gut 2004; 53:641–648.
7. Aine L, Mäki M, Reunala T. Coeliac-type dental enamel defects in patients with dermatitis herpetiformis. Acta Derm Venereol 1992; 72:25–27.
8. Reunala T, Kosnai I, Karpati S, et al
. Dermatitis herpetiformis: jejunal findings and skin response to gluten-free diet. Arch Dis Child 1984; 59:517–522.
9. Hervonen K, Karell K, Holopainen P, et al
. Concordance of dermatitis herpetiformis and celiac disease in monozygous twins. J Invest Dermatol 2000; 115:990–993.
10. Kaukinen K, Collin P, Mäki M. Latent coeliac disease or coeliac disease beyond villous atrophy? Gut 2007; 56:1339–1340.
11. Meeuvisse GW. Diagnostic criteria in coeliac disease. Acta Paediatr Scand 1970; 45:523–526.
12. Matysiak-Budnik T, Malamut G, de Serre N, et al
. Long-term follow-up of 61 coeliac patients diagnosed in childhood: evolution toward latency is possible on a normal diet. Gut 2007; 56:1379–1386.
13. Högberg L, Stenhammar L, Wågenmark J. Very late mucosal relapse in a girl with coeliac disease. Acta Paediatr 1993; 82:887–899.
14. Lundin KE. Commentary: transient coeliac disease back on stage again? Scand J Gastroenterol 2005; 40:1137–1139.
15. Croft N. Gluten-free diets in celiac disease: does life mean life? Gastroenterology 2008; 134:883–885.
16. Simell S, Kupila A, Hoppu S, et al
. Natural history of transglutaminase autoantibodies and mucosal changes in children carrying HLA-conferred celiac disease susceptibility. Scand J Gastroenterol 2005; 40:1182–1191.
17. Mustalahti K, Collin P, Sievänen H, et al
. Osteopenia in patients with clinically silent coeliac disease warrants screening. Lancet 1999; 354:744–745.
18. Viljamaa M, Collin P, Huhtala H, et al
. Is coeliac disease screening in risk groups justified? A fourteen-year follow-up with special focus on compliance and quality of life. Aliment Pharmacol Ther 2005; 22:317–324.
19. Tau C, Mautalen C, De Rosa S, et al
. Bone mineral density in children with celiac disease: effect of a gluten-free diet. Eur J Clin Nutr 2006; 60:358–363.
© 2008 Lippincott Williams & Wilkins, Inc.
This article has been cited
Current Opinion in PediatricsPediatric celiac diseaseCurrent Opinion in Pediatrics