Although refractory celiac disease (RCD) is frequently suspected, alternative or additional diagnoses can often explain the patient’s symptoms. First, it is important to carefully review the original diagnosis, especially the biopsy slides and serology. The absence of the specific gene pairs associated with CD risk, DQA1*05:DQB1*02 (DQ2) or DQA1*03:DQB1*0302(DQ8), makes CD unlikely. RCD is categorized into type I (polyclonal phenotype) and type II (clonal expansion of an aberrant intraepithelial T-cell population). The monoclonal phenotype can be detected by immunohistochemical analysis of intraepithelial lymphocytes, which will have cytoplasmic CD3 but lack the typical surface markers of T cells, including CD8, CD4, and T-cell receptor–βF1. T-cell receptor gene rearrangement analysis by PCR on extracted DNA from intestinal biopsies is an alternative method of identifying a T-cell clone, as in this case report. Although sufficient DNA for PCR can usually be obtained from fixed biopsies, we find that fresh frozen samples have a better yield of DNA, making possible Southern blotting in addition to the sensitive but less specific PCR technique. It also should be noted that DNA extraction destroys the tissue blocks, so immunohistochemical analysis should be performed first. Identification of clonal transformation of intraepithelial lymphocytes by flow cytometry has recently been used as an alternative method for diagnosis.
The diagnosis of type II RCD has significant clinical implications. T-cell clonal transformation is typically viewed as an initial step along a continuum leading to overt enteropathy-associated T-cell lymphoma (EATL). Development of EATL is common among RCD II patients and is associated with a high mortality rate. The use of immunosuppressive drugs in RCD II patients is controversial because of the theoretical risk of accelerating the transformation to lymphoma. A recent aggressive approach using myeloablative chemotherapy followed by autologous stem cell support has been used in patients with RCD II with early results that appear encouraging. More recently, budesonide has been shown to improve overall clinical symptoms among both RCD I and II groups and to minimize the adverse side effects associated with chronic immunosuppression. Despite treatment, patients with RCD II frequently clinically deteriorate from complications of severe malnutrition. As aptly illustrated by Mikesh et al., nonresponsive celiac disease is a challenging condition.
Grant/funding Support: S.H.B. is supported by the NIH training grant T32 DK07198. J.A.M. is supported by NIH grants DK57892 and 071003.
Financial Disclosures: J.A.M. has been a consultant to Astra Zeneca, Alvine Inc., and Novartis and an investigator for Alba Therapeutics and Dynagen Inc.
- © 2008 The American Association for Clinical Chemistry