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A new cause of 'non-responsiveness' in coeliac disease?
  1. J S R Jenningsa,
  2. J I Wyattb,
  3. P D Howdlea
  1. aSt James's University Hospital, Leeds, UK Division of Medicine, bDepartment of Pathology
  1. Professor P D Howdle, Division of Medicine, Clinical Sciences Building, St James's University Hospital, Leeds LS9 7TF, UK

Abstract

A 42 year old man presented with gluten-responsive coeliac disease and secondary pancreatic insufficiency. Subsequently his symptoms relapsed and repeat small intestinal biopsy showed villous atrophy and infiltration by leukaemic cells, despite continuation of a gluten-free diet. Serious causes of relapse and non-responsiveness in coeliac disease include enteropathy-associated T-cell lymphoma, ulcerative jejunitis and an end-stage hypoplastic mucosa. This is the first report of non-responsiveness due to infiltration by leukaemia.

  • coeliac disease
  • villous atrophy
  • gluten sensitivity
  • leukaemia

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Most patients with coeliac disease respond satisfactorily to a gluten-free diet. A small number fail to respond, either initially or after a period of treatment. There are many causes for this.1-3 In such a situation the diagnosis should be carefully reviewed and a search made for serious causes of the non-responsiveness.

Case report

A 42 year old man presented with a 6-month history of severe watery diarrhoea, dehydration and weight loss of 6.4 kg. He had previously been well, although had always had loose stools since childhood. Investigation revealed a macrocytic anaemia with a low serum folate, and subtotal villous atrophy on duodenal biopsy (figure, A). Coeliac disease was diagnosed and a gluten-free diet (GFD) was started.

Seven months later a repeat duodenal biopsy showed significant histological improvement (figure, B), suggesting mucosal gluten-responsiveness and supporting the diagnosis of coeliac disease. However, the diarrhoea was still present and failed to improve, despite the subsequent addition of a lactose-free diet, prednisolone and metronidazole. The macrocytic anaemia had progressed, despite folic acid replacement, and splenomegaly had developed. Bone marrow examination revealed chronic myelomonocytic leukaemia (CMML). He required monthly blood transfusions.

At that stage, 18 months after his initial symptoms and 11 months after starting a GFD, he was referred to us for further assessment of his diarrhoea. He still had watery diarrhoea up to 10 times per day. He was lethargic and had lost a further 6.4 kg in weight. There was no rectal bleeding or abdominal pain. On examination he was thin and wasted, with splenomegaly and mild peripheral oedema.

Investigations directed towards finding the cause of his diarrhoea included: haemoglobin 10.6 g/dl, white cell count 34 × 109/l, platelets 46 × 109/l, mean corpuscular volume 108 fl, monocytosis and leucoerythroblastic blood film; prothrombin time 23.8 s, albumin 22 g/l, alkaline phosphatase 679 IU/l, vitamins A and E decreased, ferritin 2310 μg/l, IgA antigliadin positive.

Enteroscopy showed ulceration in the second and third parts of the duodenum. Colonoscopy and small bowel enema were normal. Abdominal computed tomography (CT) scan revealed hepatosplenomegaly and low volume inguinal lymphadenopathy. Pancreolauryl test was low at 18.5% (normal >30%). A SeHCAT scan showed severe bile salt malabsorption.

The histology was reviewed. The initial small intestinal biopsy revealed villous atrophy, crypt hyperplasia and increased numbers of lamina propria and intra-epithelial lymphocytes (figure, A). These changes had improved after 7 months on a GFD (figure, B). The current duodenal and jejunal biopsies (18 months after the initial presentation and after 11 months on a GFD) show a relapse in the mucosal injury (figure, C). Infiltrating lymphocytes were seen but appeared atypical. On immunostaining they were confirmed as large monocytes. This suggested early infiltration by CMML cells. Such cells were not found on earlier slides, and these inflammatory changes were not typical of those seen in coeliac mucosa.

Treatment continued with a GFD and vitamin supplements. Pancreatic replacement therapy was commenced.

At 3-month review his symptoms had improved, with considerable resolution of his diarrhoea, and his weight had increased. However, he now required more frequent transfusions and commenced chemotherapy for his CMML.

Eight months later he was re-admitted with further weight loss and malnutrition. He remained IgA antigliadin positive. Enteroscopy revealed disease progression of the CMML in the intestinal mucosa. One month later total parenteral nutrition was commenced prior to a proposed bone marrow transplant. Unfortunately, he died from a septic episode.

The diagnosis in this case was considered to be:

  • Coeliac disease with secondary pancreatic insufficiency

  • CMML with subsequent small bowel infiltration

  • Consequential mucosal damage and bile salt malabsorption.

Discussion

In the majority of cases of coeliac disease there is an adequate clinical and histological response to a GFD.1However, a small proportion of patients (7–8%)2 fail to respond to a GFD and the mucosa remains abnormal. Non-responsiveness may be primary, ie, failure to respond from the outset to a GFD, or secondary, when previous response to gluten exclusion relapses.

The commonest cause of failure to respond to a GFD is non-compliance or inadvertent gluten intake. Once the GFD has been formally assessed and a strict diet followed with no histological improvement, other causes should be sought and the diagnosis reviewed.3-5

Serious causes of non-responsiveness should always be considered: a complicating enteropathy-associated T-cell lymphoma, an associated ulcerative jejunitis and an end-stage hypoplastic mucosa.6

This case raises several important questions. First, what was the evidence for coeliac disease? There was a suggestive history of loose stools from childhood. His symptoms certainly suggested malabsorption and he had a small intestinal mucosal abnormality compatible with coeliac disease. On gluten withdrawal the mucosa had improved considerably by 7 months, but he remained symptomatic. In an adult patient this suggests mucosal gluten-responsiveness and would normally be diagnostic of coeliac disease. This would be compatible with the definition based on small bowel pathology proposed by Booth in 19747 and now generally accepted by gastroenterologists.8 However, this patient did not initially improve clinically, he remained IgA antigliadin positive and therefore did not fulfil the revised ESPGAN criteria9 for the diagnosis of coeliac disease, albeit in children. In such cases a clinical remission is required, together with the disappearance of circulating antigliadin antibodies. If the diagnosis is in doubt, a gluten challenge is recommended. In this case, the patient was too ill to consider a gluten challenge, but also symptomatic improvement did occur with pancreatic replacement therapy. Secondary pancreatic insufficiency in coeliac disease is well-described1-3 and therefore we feel that once this had been corrected, together with the initial mucosal response to a GFD, there is good evidence for a diagnosis of coeliac disease, even though by this stage the mucosa was becoming involved by early infiltration with CMML. The persistently positive IgA antigliadin antibody would not be inconsistent with a diagnosis of coeliac disease. It can take months or even years for the titre to become negative after institution of a GFD and a remaining mucosal abnormality, whatever the cause, is likely to permit continuing excess IgA production.

Learning points

  • Coeliac disease is a common cause of malabsorption

  • Villous atrophy, crypt hyperplasia and lymphocytic infiltration of the small intestinal mucosa are characteristic

  • At least 90% of patients respond clinically and histologically to a gluten-free diet

  • Non-response to the diet, either initially or later, may be due to poor dietary compliance, incorrect diagnosis, or a serious complication

  • Serious complications include enteropathy-associated T cell lymphoma, ulcerative jejunitis or mucosal hypoplasia

The second question revolves around the subsequent mucosal relapse with recurrence of weight loss and malabsorption. This was due to the progressive involvement with CMML. It is rare for CMML to involve the gastrointestinal tract.10 We suggest that the intestinal mucosa was predisposed by coeliac disease to subsequent involvement by CMML. The bile salt malabsorption suggested extensive mucosal involvement distally by the CMML.

Thus this was a case of coeliac disease with secondary pancreatic insufficiency, where a second mucosal pathology caused further mucosal damage and apparent non-responsiveness.

References

Figure 1

A: original duodenal biopsy illustrating subtotal villous atrophy; B: following a gluten-free diet, small bowel morphology improved to near normal appearance; C: mucosal relapse showing partial villous atrophy with normal enterocytes but an increase in lamina propria cellularity due to involvement with CMML (H + E stain, orig magnification × 32).

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