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Changing Phenotype of Celiac Disease After Long-term Gluten Exposure

Kurppa, Kalle*; Koskinen, Outi*; Collin, Pekka†,§; Mäki, Markku*,§; Reunala, Timo†,‡; Kaukinen, Katri†,§

Journal of Pediatric Gastroenterology & Nutrition: October 2008 - Volume 47 - Issue 4 - p 500–503
doi: 10.1097/MPG.0b013e31817d8120
Case Reports

*Paediatric Research Centre, Finland

§Medical School, University of Tampere, Finland

Departments of Gastroenterology and Alimentary Tract Surgery, Finland

Dermatology, Tampere University Hospital, Finland

Received 4 March, 2008

Accepted 23 April, 2008

Address correspondence and reprint requests to Katri Kaukinen, MD, PhD, University of Tampere, Medical School, FIN-33014 University of Tampere, Finland (e-mail:

This study and the Celiac Disease Study Group are supported by the Academy of Finland Research Council for Health, the Competitive Research Funding of the Pirkanmaa Hospital District, the Yrjö Jahnsson Foundation, the Foundation for Paediatric Research and the Finnish Coeliac Society.

The authors report no conflicts of interest.

Celiac disease is an autoimmune disorder wherein the ingestion of gluten causes villous atrophy of the small intestinal mucosa with crypt hyperplasia in genetically susceptible individuals. The classic symptoms are malabsorption, steatorrhea, weight loss, growth retardation, and failure to thrive (1,2). Dermatitis herpetiformis is a well-known extraintestinal manifestation of celiac disease, characterized by granular immunoglobulin A (IgA) deposits in uninvolved skin (3). Approximately 17% of celiac patients have dermatitis herpetiformis (4). Celiac disease can appear at any age after gluten has been introduced into the diet, whereas dermatitis herpetiformis usually manifests in adulthood, the median age of diagnosis being about 40 years (4).

It remains obscure why some patients experience celiac disease, overt enteropathy, and no skin involvement, whereas some experience dermatitis herpetiformis with often only mild enteropathy. The following 3 case reports indicate that periods of gluten intake and gluten withdrawal may have an impact on disease expression, and the phenotype may vary in the same person over time.

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In 1970 a 6-month-old girl experienced vomiting, failure to thrive, and severe weight loss after wheat had been introduced into her diet. Endoscopy of the small bowel was performed, and biopsy of the small intestinal mucosa was suggestive of celiac disease. All of her symptoms disappeared when she consumed a gluten-free diet. One year later she was given a gluten-containing diet on her mother's decision. There were no immediate consequences, but 6 years later the child was re-examined because of recurrent abdominal pain. Small-bowel mucosal biopsy showed subtotal villous atrophy with crypt hyperplasia, and a gluten-free diet was reintroduced (Fig. 1). During follow-up she was asymptomatic, and a control endoscopy 7 years later (1984) showed recovery of the small bowel mucosal villous architecture. At that time a postpubertal gluten challenge was started as a standard procedure to confirm the diagnosis of celiac disease. After 3 years she had remained asymptomatic, and the small bowel mucosal structure was normal despite gluten consumption. Thereafter, follow-up with a gluten-containing diet took place in primary health care. Sixteen years later, at age 35, she contacted a physician because of a bullous rash on her elbows. IgA-class antiendomysial antibodies were positive, and skin biopsy indicated dermatitis herpetiformis. Small bowel mucosal biopsy showed crypt hyperplasia and partial villous atrophy (Fig. 2). Once again a gluten-free diet was introduced, with disappearance of the rash and negative seroconversion.

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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).

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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).

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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.

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