Setting Of Celiac Disease Research Articles

Lorna Macfarlane

<h3>ABSTRACT</h3> Polymorphisms in the <i>human leukocyte antigen</i> (<i>HLA</i>) genes within the <i>major histocompatibility complex</i> (<i>MHC</i>) locus strongly influence autoimmune disease risk^1–5. Two non-exclusive hypotheses exist about the pathogenic role of...

Chronic Inflammation Permanently Reshapes Tissue-Resident Immunity in Celiac Disease

Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity forthe butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing Tcell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD. VIDEO ABSTRACT.

Sprue-like Intestinal Disease

Recurrent symptoms in well-established celiac disease may result in further clinical evaluation. In most, poor diet compliance is present. Other considerations include an unidentified gluten source, an erroneous initial diagnosis, another or second and superimposed cause for symptoms, or a complication, including collagenous sprue or an intestinal lymphoma. Failure to define an initial gluten-free diet response, however, suggests that celiac disease may not be present. Instead, a distinctive enteropathic process, refractory to diet restrictions, including gluten, is evident. This “sprue-like” intestinal disorder or enteropathy remains unclassified, and probably, represents a heterogeneous entity. Molecular changes suggestive of early clonal expansion of an aberrant population of intra-epithelial lymphocytes may be detected in some (with or without a prior gluten-free diet response), and these changes may signify an early or “cryptic” lymphoma. Other newly recognized lymphoproliferative disorders occurring in the setting of celiac disease have been recorded, including hepatosplenic delta-gamma T-cell lymphoma, an indolent CD4+ T-cell lymphoma, particularly in younger males, and large granular lymphocytic leukemia, a possibly treatable disorder characterized by the clonal expansion of T-cells in blood and small intestinal mucosa. Studies using IL-15 blockade in a transgenic mouse model with pathologic features of a sprue-like intestinal disease has led to human clinical trials with encouraging positive results.

Incidence and Outcomes of Neutropenia in Patients with Celiac Disease- a Consecutive Analysis of 1729 Patients

▪Background: Celiac disease (gluten sensitive enteropathy) is a systemic disease with hematological manifestations including; iron deficiency anemia, vitamin B12 and folate deficiency, leukopenia/neutropenia, hyposplenism, venous thromboembolism, and the enteropathy associated T cell lymphoma (E-TCL). Leukopenia/neutropenia is rare, and can result from folate or copper deficiency, but in many cases remains idiopathic. The consequences of neutropenia and neutrophil responses to a gluten free diet are not well described. We carried out this study to assess the incidence and outcomes of neutropenia in patients with celiac disease.Methods: The Mayo clinic celiac disease database (n=1729) was retrospectively analyzed for all patients with a confirmed diagnosis of celiac disease that had leukopenia (<3.5 x10(9)/L) and/or neutropenia (<1.5 x 10(9)/L). The diagnosis of celiac disease was established by positive tissue transglutaminase antibodies (TTG) and confirmatory small bowel biopsy findings. Additional causes of neutropenia such as copper and folate deficiency, drugs, benign ethnic and cyclic neutropenia, chemotherapy, hematological malignancies, combined variable immunodeficiency (CVID), and autoimmune diseases were meticulously excluded. Data abstracted included demographics, temporal association with diagnosis, nadir counts, associated hematological findings, relationship with infections, the use and effect of G-CSF, response to gluten free diet and survival outcomes.Results: 21(1.2%) of 1729 cases screened had idiopathic-celiac related neutropenia; 17 (81%) Caucasian, 15 (48%) females. In 12(57%) patients the neutropenia preceded or occurred near the time of the diagnosis of celiac disease, while in 7 (33.3%) it occurred subsequently. In 2 cases the temporal association could not be established. The median age at diagnosis of celiac disease was 46 years (10-67) and the median follow up for this group was 41.7 months (0-207.3). At last follow up 1 (4.8%) death has been documented; 0 from infectious complications, with no cases of E-TCL. The median laboratory values at diagnosis of celiac disease were available in 11 (52%) patients and included; hemoglobin 12.9 g/dL (10.5-16.8), MCV 91.5 fl (79.6-102.8), WBC 3.2 x109/L (2.3-5.2), ANC 1.29x109/L (0.33-3.24), ALC 1.34x109/L (0.75-2.17), AMC 0.39x109/L (0.15-0.71), and platelet counts 225x109/L (168-711). Anti-granulocyte antibodies were assessed in 7 patients and were negative in all cases. None of these patients had coexistent hyposplenism and three cases of neutropenia that occurred in the setting of celiac disease and CVID were excluded. In 15 (71%) patients the neutropenia was incidentally detected during routine laboratory work and in 4 (19%) it came to light secondary to infections. Ten (48%) patients had recurrent infections (≥1) as documented by their providers, including 7 with sinopulmonary infections, 1 with urinary tract infections, and 1 with skin and soft tissue infections. Additional immunological assessments were not available in these patients.Three (14%) patients had an ANC <500 (significant neutropenia); of which 2 had recurrent sinopulmonary infections. The third patient remained largely asymptomatic. Two of the 3 patients received G-CSF support during infections and responded adequately (ANC improvement > 1 x 10(9)/L). The ANC in patients in this cohort did not correlate with severity of infections. Five (23%) of 21 patients had improvement in neutrophil counts after adopting a gluten free diet, while there was no response in 10 and data was unavailable in 6. The median time to ANC response was 14.5 months (10-15.3) and the median increment in ANC was 0.67 x 10(9)/L (0.48-0.98).Conclusions: Celiac disease associated neutropenia, especially significant neutropenia (ANC <500) is a rare occurrence (~1%). It can often pre-date the diagnosis of celiac disease or occur subsequently. It is potentially associated with an increased incidence of infections, with-out good correlation with the severity of neutropenia. Less than half the patients do seem to respond to a gluten free diet. G-CSF responses seem to be adequate and G-CSF can be used in the setting of severe infections. DisclosuresNo relevant conflicts of interest to declare.

Acute abdomen in a patient with coeliac disease: a case report and literature review of enteropathy-associated T-cell lymphoma (EATl)

A 71-year-old female with a history of poorly-controlled coeliac disease presented with worsening symptoms of small bowel obstruction over 3 weeks. Jejunal, ileal and mesenteric resections were performed. The patient did not recover after surgery and died 3 weeks later. Patchy mucosal ulcerative plaques were seen, corresponding to transmural infiltration by medium-to-large atypical lymphoid cells positive with CD3 and CD56 but negative for CD5, CD8, CD4 and CD20. Similar atypical cells were identified in all regional lymph nodes, in a predominantly sinusoidal distribution. Remaining small bowel mucosa showed typical histological features of coeliac disease, comprising severe villous atrophy, intraepithelial lymphocytosis (reactive lymphocytes) and crypt hyperplasia. EATL of the small intestine with involvement of mesenteric lymph nodes, occurring in the setting of coeliac disease, was diagnosed. EATL is an uncommon lymphoma of intraepithelial T-lymphocytes mostly occurring in patients with coeliac disease. Ten to twenty percent of cases may occur sporadically without coeliac disease (type II EATL) in which monomorphic, medium-sized cells are present. Type II EATL has a distinctive immunophenotype. Both EATL types have very poor prognosis due to low tumour chemosensitivity and aggressive behaviour. Major postsurgical complications are also common in patients who are nutritionally deficient due to coeliac disease.

Small bowel adenocarcinoma complicating coeliac disease: a report of three cases and the literature review.

Coeliac disease is associated with an increased risk of malignancy, not only of intestinal lymphoma but also of small intestinal adenocarcinoma which is 82 times more common in patients with celiac disease than in the normal population. We report three additional cases of a small bowel adenocarcinoma in the setting of coeliac disease in order to underline the epidemiological features, clinicopathological findings, and therapeutic approaches of this entity based on a review of the literature. The three patients underwent a surgical treatment followed by adjuvant chemotherapy based on capecitabine/oxaliplatin regimen, and they have well recovered.

Whole-Genome Analysis and HLA Genotyping of Enteropathy-Type T-Cell Lymphoma Reveals 2 Distinct Lymphoma Subtypes

Enteropathy-type T-cell lymphoma (ETL) is an aggressive extranodal T-cell non-Hodgkin lymphoma assumed to arise in the setting of celiac disease. To precisely define the genetic alterations underlying the pathogenesis of ETL, 30 ETL samples were profiled for genetic copy number alterations using high-resolution whole-genome tiling path array comparative genomic hybridization. To investigate the potential association of genetic alterations in ETL with celiac disease, HLA-DQB1 genotyping was performed. By array comparative genomic hybridization, 13 novel recurrent minimal regions of chromosomal alteration were identified on multiple chromosome arms. ETL is characterized by frequent complex gains of 9q31.3-qter (70% of cases), or by an almost mutually exclusive 2.5-megabase loss of 16q12.1 (23% of cases). Two distinct groups of ETL could be delineated morphologically and genetically: type 1 ETL is characterized by nonmonomorphic cytomorphology, CD56 negativity, and chromosomal gains of 1q and 5q. Type 1 ETL also appears to be linked pathogenetically to celiac disease, sharing genetic alterations and HLA-DQB1 genotype patterns with (refractory) celiac disease. Type 2 ETL shows monomorphic small- to medium-sized tumor cell morphology, frequently shows CD56 expression, MYC oncogene locus gain, and rare gains of chromosomes 1q and 5q. In contrast to type 1 ETL, type 2 ETL shows a HLA-DQB1 genotype pattern more resembling that of the normal Caucasian population. Contrary to current clinical classification, ETL comprises 2 morphologically, clinically, and genetically distinct lymphoma entities. In addition, type 2 ETL may not be associated with celiac disease.

Diffuse Small Bowel Inflammation

Diffuse small intestinal inflammation is a rare finding which presents a diagnostic conundrum for most physicians. Its differential diagnosis includes conditions ranging from gastroenteritis to lymphoma. Ulcerative jejunitis (UJ) is a poorly understood disorder, which usually presents in the setting of celiac disease, and often is a harbinger of small bowel lymphoma. We present one of the few cases in medical literature of a patient, who developed UJ with a modest response to treatment with corticosteroids. The patient is a healthy 50-year old African American female who presented with a history of nausea, vomiting, and abdominal pain of one day's duration. The pain, described as tightness, was localized to the periumbilical and epigastric regions. The pain was quickly followed by vomiting and watery diarrhea. There was no obvious bleeding. These symptoms were followed by chills and low-grade fever. CT scan of the abdomen on admission revealed diffuse small bowel inflammation from the ligament of Treitz to the proximal ileum. Routine stool studies were negative. Anti-transglutaminase antibodies were negative. A push enteroscopy revealed severe ulceration and edema from the distal duodenum to the extent of the enteroscope. Biopsies revealed edema, abundant exudation, and some lymphocytic infiltration, compatible with chronic jejunitis. There were no granulomas, giant cells, vasculitis, or lymphoma. After a prolonged hospital stay marked by persistent symptoms, parenteral nutrition, a repeat enteroscopy, and a laparoscopic exploration, she was started on corticosteroids, which resulted in slow improvement but progressive improvement. UJ is a rare condition characterized by small bowel ulcerations, edema, abdominal pain, and malabsorption in the absence of any other etiology. Severe malabsorption leads to malnutrition and wasting. Malignant transformation into T-cell lymphoma is more common in the setting of celiac sprue. Early diagnosis, based on characteristic clinical, endoscopic, and histologic findings leads to early institution of corticosteroids. Corticosteroids are the mainstay of treatment, but are at best only moderately effective. Untreated, the prognosis is extremely poor, thus early recognition is imperative. Small bowel edema portends a difficult differential diagnosis to investigate. Ulcerative jejunitis may lead to malnutrtion and T cell lymphoma. Early recognition and treatment with corticosteroids is imperative to attempt to minimize risk of these complications.

Celiac Sprue Associated Membranoproliferative Glomerulonephritis

A 50 year old hispanic male with hypertension, urticaria pigmentosa, vitamin B 12 deficiency and anemia was evaluated for chronic diarrhea and was diagnosed to have celiac sprue with positive antigliadin antibodies. He also complained of having a foamy urine but did not undergo formal evaluation of kidney function initially.He was started on a gluten free diet with resolution of diarrheal symptoms but kept having proteinuria and soon developed swelling of both his lower extremities. Subsequent evaluation revealed the presence of nephrotic syndrome with a 24 hour urine protein of 4.7 gms. He had a serum creatinine of 1.2mg/dl, Hemoglobin of 10.5 g/dl, low C3 and normal C4 levels. A kidney biopsy performed diagnosed him to have membranoproliferative glomerulonephritis(MPGN). He was started on PO steroids (without any cytotoxic agents) which he received for 6 months. He responded to treatment after six months of therapy and has stayed in disease remission. Celiac sprue is a common cause of malabsorption in Caucasians, and the etiology of the disease is suspected to involve environmental, immunologic and genetic factors. The immunologic components suspected are the IgA antibodies (IgA antigliadin, IgA antiendomysial and IgA anti-tissue transglutaminase). Circulating immune complexes have been noted to be deposited in the kidney and are occasionally implicated in causing IgA nephropathy. But the occurence of MPGN in the setting of Celiac disease is more infrequent. We report this rare occurence of MPGN in a patient with celiac disease. The potential significance of identifying patients with celiac disease to have MPGN may have important implications to understanding the etiology of these diseases. This case suggests that the possible source of antigen in celiac disease with MPGN may be of a dietary origin which required treatment with steroids to maintain remission of disease.

Benign Pneumatosis Intestinalis in the Setting of Celiac Disease

Pneumatosis intestinalis is an uncommon finding that may indicate the presence of several alarming pathological conditions, including bowel ischemia, that require urgent surgical intervention. We report the case of a 51-year-old man with celiac disease who underwent resection of a large duodenal adenocarcinoma. Although he initially recovered rapidly from his procedure, he subsequently developed abdominal distention and leukocytosis. Abdominal imaging revealed extensive small bowel pneumatosis and pneumoperitoneum. Emergent surgical exploration revealed only bowel wall air cysts and dilated bowel but failed to demonstrate any intra-abdominal pathology. The patient recovered uneventfully and was discharged without any further complications or recurrence of symptoms. We review the current literature on the rare finding of pneumatosis intestinalis in the setting of celiac disease. In all reported cases, even when pneumatosis is accompanied by pneumoperitoneum, these alarming findings have proved to be of "benign" origin, that is with no evidence of bowel ischemia, perforation, or peritonitis. The available evidence suggests that pneumatosis in the setting of celiac disease may reflect the dissection of intraluminal gas into the inflamed bowel wall without accompanying intra-abdominal pathology. We conclude that pneumatosis intestinalis, even with accompanying pneumoperitoneum, does not uniformly mandate surgical exploration in patients with celiac disease.

Genetic testing: Who should do the testing and what is the role of genetic testing in the setting of celiac disease?

Celiac disease is a remarkable and common immune-mediated disorder determined by both the presence of characteristic HLA alleles (DQ2 and DQ8) and one of the best characterized environmental factors (gliadin) for any common autoimmune disease. The discovery of transglutaminase autoantibodies and the development of assays for these antibodies has allowed the identification of a large number of asymptomatic individuals with autoimmunity and intestinal biopsy evidence of celiac lesions. Further understanding of the sequelae of asymptomatic celiac disease, and the interaction between genetic susceptibility and environmental factors, are likely to alter fundamentally both genetic screening for celiac disease and its therapy.

8 The major complications of coeliac disease

Neoplasms constitute the major complication of coeliac disease, and highgrade T-cell lymphoma of the small intestine (enteropathy-associated T-cell lymphoma) is the most common neoplasm in this category. HLA genotyping indicates that in patients with enteropathy-associated T-cell lymphoma have the coeliac disease associated DQA1∗0501, DQB1∗0201 phenotype, although additional HLA-DR/DQ alleles may represent risk factors for lymphoma development. Molecular biological and immunohistochemical studies have shown that the intestinal mucosa distant from the tumour contains clonal populations of small T cells, often of the same clone as the high-grade T-cell lymphoma. These findings suggest that enteropathyassociated T-cell lymphoma arises in the setting of coeliac disease and evolves from reactive intraepithelial lymphocytes through a low-grade lymphocytic neoplasm to a high-grade tumour, which is usually the cause of the presenting symptoms. Most cases of chronic ulcerative enteropathy (ulcerative jejunitis) are probably part of the same disease process. If the ulceration occurs at a time when the neoplastic T-cells are of a low grade, morphological recognition of tumour cells in the ulcers may be impossible. Carcinoma of the pharynx and oesophagus, and adenocarcinoma of the small intestine, are increased in frequency in patients with coeliac disease. The increased risk of carcinoma of the oesophagus may be related to vitamin A deficiency. A number of reports have indicated an increased prevalence of various types of chronic hepatitis in patients with coeliac disease, but no coherent view of the cause of this association has emerged. Similarly, patients with coeliac disease have been reported to have various forms of fibrosing lung disease of uncertain causation. In recent years, there have been several reports, mainly from Italy, of a syndrome of epilepsy and bilateral brain calcification occurring in coeliac patients. The pathogenesis of this condition is not known and its prevalence in other communities is uncertain. Splenic atrophy occurs frequently in patients with coeliac disease and is related to the severity of the disease and degree of dietary control. Splenic atrophy predisposes to infection with capsulated bacteria, although mortality studies indicate that infection with these organisms is not a major cause of death in patients with coeliac disease.

Dermatitis Herpetiformis.

Dermatitis herpetiformis (DH) is an autoimmune bullous disease, which represents the cutaneous manifestation of gluten sensitivity, in the setting of celiac disease. Although classical DH is characterized clinically by grouped, vesicles on an erythematous base, primary lesions often are absent owing to the intense, associated pruritus. Instead, many cases present only with erythematous erosions with numerous overlying excoriations. As in celiac disease, the core pathogenic mechanisms of DH are likely mediated by immunoglobulin A class autoantibodies against one of several transglutaminase enzymes. As the production of these autoantibodies is directly correlated with gastrointestinal exposure to gliadin, which is an alcohol-soluble fraction of gluten, a gluten-free diet represents the cornerstone of a DH management regimen. In cases refractory to dietary management alone, dapsone is the first-line agent for the treatment of DH, although many other agents have been anecdotally reported as effective.