Case report of a child with latent coeliac disease
In this issue of the European Journal of Gastroenterology and Hepatology, Carroccio et al.  report the case history of an infant who, at the age of 1 year, developed diarrhoea but was not investigated until he was 25 months old. At this time antigliadin and endomysial antibodies were detected in the serum. A biopsy from the proximal jejunum showed partial villous atrophy with a villus:crypt ratio of 1:1 and a marked increase in intraepithelial lymphocytes (IELs). Giardia lamblia was found in aspirates of the intestinal fluid. A diagnosis of coeliac disease with giardiasis was made. A course of metronidazole was given and a gluten-free diet (GFD) recommended. At follow-up 2 months later, it was learned that the diarrhoea had settled within 7 days of receiving metronidazole, but a GFD had not been started. Antigliadin and endomysial antibodies were still present but in lower titres. It was decided that the child should continue with a normal diet, and at review 6 months later he was noted to be well and growing satisfactorily. Serum antibodies had disappeared and a repeat intestinal biopsy was structurally normal with only a slight increase in IELs. At the age of 4 years the child was still well with negative serological tests for coeliac disease. His human leucocyte antigen (HLA) phenotype was characteristic of coeliac disease. A third jejunal biopsy showed normal villous architecture but the epithelial CD3+ lymphocyte count was 40 and the γ/δ+ lymphocyte count 13.7 (normal values <25 and <3.2, respectively). Giardia was absent from the intestinal fluid. At this time, when antibodies had disappeared from the serum, endomysial antibodies were detected in the supernatant fluid from cultures of the intestinal mucosa. Blood taken and stored at the original presentation was found to contain immunoglobulin (Ig)A anti-tissue transglutaminase antibodies (anti-tTG). The child continued to prosper on a normal diet equating to an average intake of gluten of 11 g/day. The authors regard him as a patient with latent coeliac disease.
Early definitions of coeliac disease revolved around abnormalities in the upper small bowel, comprising total or severe partial villous atrophy and the responses, both clinical and morphological, to gluten withdrawal and ingestion . However, with expanding knowledge of the natural history of coeliac disease, the controversial issue of whether this disorder could be diagnosed in the absence of the classical flat biopsy was increasingly debated. For almost 30 years there has been evidence that an increased cellular infiltrate in an otherwise normal jejunal mucosa from patients with dermatitis herpetiformis indicates gluten sensitivity . In an important paper, Weinstein in 1974  took the story further when he identified two patients with dermatitis herpetiformis who, on a normal diet containing 7–10 g of gluten per day, had normal jejunal biopsies. When the dietary gluten load was increased to 20 g each day, both patients developed patchy abnormalities of the mucosa comprising a reduction in villous height, an increase in crypt depth, alterations in the epithelium and an increase in the cellular infiltrate in the mucosa. In one case, the mucosa reverted to normal when the gluten load was reduced. These observations led to the conclusion that a latent form of coeliac disease exists that can be unmasked by giving a high gluten diet. The question was asked whether patients with latent coeliac disease might develop a flat mucosa and symptoms at some time in their life without a change in gluten intake.
Weinstein  wrote of overt coeliac disease in those with a flat mucosa and steatorrhoea, occult coeliac disease in those with a flat mucosa but no steatorrhoea and latent coeliac disease. He considered that the presence or absence of steatorrhoea correlated with the length of damaged small bowel. This study provided evidence for the transition – normal mucosa to abnormal and back again – that would be expected intuitively. Support for this concept of latent coeliac disease came from a further challenge study in dermatitis herpetiformis  and from observations made in children. An initial small-bowel biopsy was normal in a girl who presented with growth retardation and anaemia, but 14 months later changes consistent with coeliac disease were evident . The mucosal architecture improved on GFD and deteriorated during gluten challenge. Others have made similar observations [7,8].
Latent coeliac disease is defined by a normal biopsy in patients taking a normal diet who, at some other time, before or since, have had a flat biopsy that recovers on a GFD. Before these patients develop a flat biopsy they have the potential to do so, and the term ‘potential coeliac disease’ was proposed to define this phase of the disorder . This designation and other terms such as mimimal change enteropathy or mild enteropathy are only useful in so far as they can be defined by tests indicating gluten sensitivity as discussed below. Marsh has shown, in elegant studies, that there is a spectrum of change in the jejunal mucosa associated with gluten sensitivity that ranges from normal to a hypoplastic–atrophic lesion . The hypoplastic–atrophic state is an end-stage, irreversible abnormality that may fall within the category of enteropathy-associated T-cell lymphoma. There is a dynamic relationship between the other mucosal lesions, however, with movement in either direction depending on factors such as the amount of gluten ingested. Marsh thus moved away from defining coeliac disease in morphological terms and towards immunological events indicating gluten sensitivity. For the purposes of this article, however, the descriptive terms latent and potential coeliac disease will be employed because these are widely used in publications. Patients with latent and potential coeliac disease are usually encountered by chance when small-bowel biopsies are taken at opportune times and are available for review.
Markers of potential and latent coeliac disease
While the villi may appear macroscopically normal in potential and latent coeliac disease, subtle changes can be present, such as an increase in IELs [7,11], minor morphometrically measured abnormalities , an increase in γ/δ T-cell receptor-bearing lymphocytes even when the IEL count is normal and an increase in the number of IELs expressing the surface antigen CD3 .
Serological tests and other immunological indices have helped to identify potential and latent coeliac disease. In a multi-centre study of 19 patients from Italy, markers of latent coeliac disease were sought . It was concluded that raised IELs and antigliadin antibodies are not always present, but endomysial antibodies are likely to be the best predictor of evolution to a flat mucosa. This latter suggestion was supported by an observation that seven children with normal mucosa and endomysial antibodies, on rebiopsy between 1 and 3 years later, had all developed villous atrophy . Of 25 individuals with antireticulin antibodies and normal mucosa, seven had progressed to a flat mucosa after a follow-up of 1–7 years . In a study of 75 healthy, first-degree relatives of patients with coeliac disease, 64 were found to have normal jejunal morphology . In many of the normal biopsies from relatives, the epithelial staining for HLA-DP (27 of 63) and HLA-DR (30 of 62) was more marked than that in the control group (3 of 19). Interleukin-2-positive cells (CD25) were not found in the epithelium from controls but were present in 24 out of 54 family members with normal mucosa. It was suggested that these changes, together with the coeliac disease marker DQ genes, may indicate potential coeliac disease in these relatives. Small intestinal biopsies from patients with coeliac disease on a GFD, challenged in vitro with gliadin peptides, were shown to produce endomysial antibodies, an observation that could be exploited in detecting potential coeliac disease . Mucosal production of endomysial antibodies may be more sensitive than the measurement of serum endomysial antibodies, which is low in patients with only mild mucosal changes . Mucosal immune activation as assessed by enhanced expression of intercellular adhesion molecule (ICAM)-1, lamina propria mononuclear cells bearing CD25 or CD80 and DR in the crypts has been found in patients with endomysial antibodies and normal jejunal mucosa architecture . Interferon (IFN)-γ is produced in large amounts in vitro by jejunal mucosa from patients with untreated coeliac disease and from those on a GFD challenged by gluten . This may also be a means of identifying potential coeliac disease. When several tests were employed to detect latent coeliac disease, the two best tests appeared to be a positive coeliac-like antibody pattern (defined as a combination of IgM antigliadin antibodies in jejunal fluid plus at least two of three other characteristic antibodies to gluten, ovalbumin and β-lactoglobulin) and a high γ/δ cell count [19,20]. This antibody pattern has been found in patients with dermatitis herpetiformis who, on a gluten-containing diet, have normal jejunal morphology . This supports its role in identifying those with potential coeliac disease.
Coeliac disease patients in clinical remission and with normal small intestinal morphology on a GFD show a persistent defect in intestinal permeability. Therefore, this intestinal permeability index could possibly be used to detect potential coeliac disease , as could the method of rectal challenge by gluten .
Clinical features of potential and latent coeliac disease and response to gluten-free diet
In 1980, we reported eight patients with abdominal pain and troublesome diarrhoea whose symptoms improved dramatically on a GFD and returned on gluten challenge . Jejunal biopsies showed only minor changes in cellularity, which also improved on gluten withdrawal. It was concluded at this time that these patients had gluten-sensitive diarrhoea but no evidence of coeliac disease. Nine non-coeliac disease, non-dermatitis herpetiformis patients, eight of whom had the coeliac-like intestinal antibody, were treated with a GFD . Within 1–2 weeks of starting the GFD, chronic diarrhoea in five patients had settled. Ten patients were investigated who presented with symptoms suggestive of coeliac disease . All had normal small-bowel biopsies on routine histological examination, although four showed an increase in IELs. Serum endomysial antibodies were present in all ten patients. The clinical and immunological features in these cases were shown, by gluten withdrawal and challenge studies, to be gluten dependent. It was suggested that these patients had latent coeliac disease but, because they had never had flat biopsies, they would be classed more correctly as potential coeliacs. It was suggested that patients presenting in this way should undergo multiple biopsies because the lesions may be patchy. Features of immune activation should also be sought and, if present, a GFD tried. Very few hospital laboratories, however, will at present be able to offer this service. While patients may have symptoms, it is not known whether they are prone to the complications associated with active coeliac disease. There is a report of lymphoma complicating latent coeliac disease .
Groups at risk of having potential and latent coeliac disease
Patients with type 1 diabetes , members of coeliac families [14,27] and those with dermatitis herpetiformis  would be expected particularly to harbour these forms of coeliac disease.
Patients with type 1 diabetes mellitus may have latent or potential coeliac disease, and consideration of these patients illustrates some important aspects of these forms of coeliac disease. In a study of 238 children with diabetes, 16 were positive for IgA antigliadin antibodies but 11 of these were negative at the first screening . Nine patients, all with antireticulin antibodies (ARA), had small intestinal biopsies characteristic of coeliac disease. In four children found to have coeliac disease and with ARA, earlier serological tests had been negative so biopsies were not taken. The histories of two of these children are instructive. Both of them, at their diagnosis of diabetes, had normal biopsies and were negative for ARA. After 1 year, one child had an ARA titre of 1:100 but the biopsy was again normal. After a further year, the ARA titre had risen to 1:200 and the small-bowel mucosa was now flat, thus confirming that the child had latent coeliac disease. The other child subsequently developed ARA but, after 8 years of follow-up, the mucosa still appeared normal. However, a ten-fold increase in the density of IEL cells bearing the γ/δ T-cell receptor was found, as well as aberrant HLA-DR expression in the crypt epithelial cells. This patient, therefore, had potential coeliac disease and required further follow-up. These cases illustrate aspects of latent and potential coeliac disease and the importance of serial testing not only in those with type 1 diabetes  but others where the suspicion of coeliac disease remains even after a normal biopsy. Relatives of patients with coeliac disease are a group at risk of developing coeliac disease themselves and may have an increase in γ/δ IELs and, therefore, potential coeliac disease .
Lessons from this case
There is no doubt that the child in this case report  has coeliac disease, as shown by: the presence of the DQw2 haplotype, serum antigliadin antibodies, endomysial antibodies and anti-tTG; an abnormal small-bowel biopsy with elevated IELs, CD3 and γ/δ cells; and in vitro intestinal production of endomysial antibodies. It is evident from clinical observation that coeliac disease can be precipitated by stresses such as gastrointestinal infection, an operation or pregnancy. In this instance, infection with G. lamblia damaged the mucosa and, when this was eradicated, the mucosa recovered without recourse to a GFD. The patient then moved from being an active to a latent coeliac disease patient. If a GFD had been followed in this case it would have been claimed that this diet caused the return to health and a normal biopsy. In the event, the patient did not follow a GFD, and this illustrates that the mucosa can be affected by factors other than gluten. It is possible that, with an appropriate stress, the patient might again develop a flat mucosa and active coeliac disease, so careful follow-up is required with measurement of serum antibodies and further biopsies should any concerns arise.
Patients with potential coeliac disease may develop symptoms that respond to a GFD. Symptoms occur presumably because the mucosa, while morphologically normal, is functionally abnormal. Before putting patients with unexplained diarrhoea on a GFD, evidence of gluten sensitivity, which can now be ascertained, should be sought. Otherwise, individuals may be given a GFD unnecessarily. Unfortunately, only a very few laboratories can offer the appropriate tests at the present time. Perhaps regional laboratories should be identified where these investigations can be concentrated. Finally, a normal small-bowel biopsy does not exclude coeliac disease for life, and repeat examinations of the mucosa are warranted, especially if there are suggestive features of the disorder and/or serological tests become or remain abnormal.
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