Risk of Morbidity in Contemporary Celiac Disease

Nina R Lewis; Geoffrey KT Holmes

Disclosures

Expert Rev Gastroenterol Hepatol. 2010;4(6):767-780. 

In This Article

Refractory Celiac Disease

Nonresponsive celiac disease (NRCD) has historically been described as a failure to respond to treatment with a gluten-free diet and can be described as primary NRCD (the celiac never responds to a gluten-free diet) or secondary NRCD (response is lost after initial improvement with recurrence of symptoms after 1 year).[80] Depending on study design and study population selected, the prevalence of NRCD is approximately 15–30%.[81] The majority of cases of NRCD are probably related to continued gluten exposure: inadvertent ingestion of small but immunologically significant amounts or nonadherence.[82] Having confirmed the index diagnosis of celiac disease holds true and established adherence to a gluten-free diet,[83] other causes of symptoms need excluding. This includes conditions associated with celiac disease that are amenable to treatment, such as microscopic colitis, pancreatic insufficiency, irritable bowel syndrome, small bowel bacterial overgrowth, thyroid dysfunction and lactose intolerance.[81,82] Some of these have been mentioned in this article.

Rarely, however, patients (perhaps only 1–2% of all cases) are described as having refractory celiac disease when symptoms persist (primary) or recur (secondary) despite the adherence to a strict gluten-free diet and when other causes have been excluded.[80] Refractory celiac disease is subdivided into types I and II.[84] Type 1 (25% of cases of refractory celiac disease) has a phenotypically normal intraepithelial T-cell population on duodenal histology and carries a good prognosis. Steroids and azathioprine are effective and the 5-year survival is over 90%. In type 2 refractory celiac disease, there is an aberrant intraepithelial T-cell population that carries intracytoplasmic but not surface CD3, usually lacks CD8 and has clonal rearrangements of the T-cell receptor-γ gene. Prognosis for patients with type 2 refractory celiac disease is poor, with the condition appearing to be largely resistant to treatment, and transition to enteropathy-associated T-cell lymphoma is common.[84–86] The 5-year survival in type 1 was 96%, but in type 2 disease was reported to be 58%, falling to 8% in the 26 patients (52%) who developed enteropathy-associated T-cell lymphoma.[85] Enteropathy-associated T-cell lymphoma can arise directly from aberrant intraepithelial T-cell lymphocytes or after passing through a stage of refractory celiac disease that manifests as chronic ulcerative jejunoileitis.

For clinicians, the challenge is to identify these entities and distinguish them from simply poor adherence to a gluten-free diet. Weight loss has been observed to be predictive of refractory celiac disease,[82] with severe malnutrition, malabsorption and hypoalbuminemia being the typical presenting features.[87] Tests that service laboratories can carry out are available and can be helpful in making this differentiation.[88] Duodenal biopsy should be assessed for T-helper:suppressor cell ratio; one way of differentiating patients with refractory celiac disease from those who do not have refractory celiac disease.[89] A predominance of T-suppressor-cytotoxic cells is consistent with untreated 'normal' celiac disease and continued exposure to gluten. Specialist centers offer assessment for aberrant clonal T-cell proliferation. Small bowel imaging, such as the use of MRI enteroclysis and CT scanning of the thorax, abdomen and pelvis, are commonly used to look for lymphoma.

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