Carolina Arguelles-Grande

Villous atrophy and negative celiac serology: a diagnostic and therapeutic dilemma.

OBJECTIVES:Patients with villous atrophy (VA) and negative celiac disease (CD) serologies pose a diagnostic and therapeutic dilemma. When a definitive etiology for VA is not determined, patients are characterized as having unclassified sprue (US), the optimal management of which is unknown.METHODS:We studied adult patients with VA on biopsy and negative celiac serologies, evaluated at our tertiary referral center over a 10-year period. Testing for HLA DQ2/8 alleles, antienterocyte antibodies, giardia stool antigen, bacterial overgrowth, total serum immunoglobulins, and HIV was noted. Treatment, response, and repeat-biopsy findings were recorded.RESULTS:The most common diagnoses of the 72 patients were seronegative CD, medication-related villous atrophy, and US. Of those with US, the majority reported symptomatic improvement with immunosuppressive therapy. Some patients initially labeled as unclassified were found to have VA associated with olmesartan use.CONCLUSIONS:The role of medications in the development of VA and the optimal dose and length of immunosuppression for patients with US should be investigated further.

Variability in small bowel histopathology reporting between different pathology practice settings: impact on the diagnosis of coeliac disease

Background and Aims Coeliac disease (CD) diagnosis requires the detection of characteristic histological alterations of small bowel mucosa, which are prone to interobserver variability. This study evaluated the agreement in biopsy interpretation between different pathology practice types. Methods Biopsies from community hospitals (n=46), university hospitals (n=18) and commercial laboratories (n=38) were blindly assessed by a pathologist at our institution for differences in histopathology reporting and agreement in diagnosis of CD and degree of villous atrophy (VA) by κ analysis. Results Agreement for primary diagnosis was very good between this institution and university hospitals (κ=0.888), but moderate compared with community hospitals (κ=0.465) or commercial laboratories (κ=0.419). Diagnosis differed in 26 (25%) cases, leading to a 20% increase in CD diagnosis after review. Among those diagnosed with CD by both institutions (n=49), agreement in degree of VA was fair (κ=0.292), with moderate agreement between the authors and commercial laboratories (κ=0.500) and fair with university hospitals (κ=0.290) or community hospitals (κ=0.211). The degree of VA was upgraded in 27% and downgraded in 2%. Within different Marsh score categories, agreement was poor (κ<0.0316) for scores 1 and 2, both missed at other centres, and fair or moderate for scores 3a and 3b. Information regarding degree of VA and intraepithelial lymphocytosis was lacking in 26% and 86% of reports and non-quantifiable descriptors, eg, ‘blunting’ or ‘marked atrophy’ were prevalent. Conclusions CD-related histological changes are underdiagnosed in community-based hospitals and commercial pathology laboratories. Because incorrect biopsy interpretation can cause underdiagnosis of CD, greater CD awareness and uniformity in small bowel biopsy reporting is required among pathologists.

Olmesartan-associated sprue-like enteropathy: a systematic review with emphasis on histopathology

Sprue-like enteropathy associated with the angiotensin II receptor blocker (ARB) olmesartan was first described in 2012, and a number of cases have since been reported. This syndrome is characterized by severe diarrhea and sprue-like histopathologic findings in the intestine, often with increased subepithelial collagen. The incidence of this adverse drug reaction is not entirely clear, although it is thought to be rare. It is also not well established if other ARBs cause such a syndrome, although case reports suggest they can. The histopathologic features of olmesartan-related injury have only been described in a limited number of cases, and there are no guidelines regarding the histopathologic distinction of olmesartan-associated enteropathy from other causes of sprue (eg, celiac disease, tropical sprue). Herein, we review the histopathologic changes and clinical observations described in recent reports of olmesartan-associated sprue-like enteropathy comprising case series and isolated reports, other relevant literature, and our experience at a referral center specializing in small intestinal disorders. We will review recent literature suggesting other ARBs can be associated with a similar phenotype. Lastly, we will discuss the histopathologic differential diagnosis and provide clues to distinguish this entity from other entities which can cause sprue-like histopathology.

Lack of Serologic Evidence to Link IgA Nephropathy with Celiac Disease or Immune Reactivity to Gluten

IgA nephropathy is the most common form of primary glomerulonephritis worldwide. Mucosal infections and food antigens, including wheat gluten, have been proposed as potential contributing environmental factors. Increased immune reactivity to gluten and/or association with celiac disease, an autoimmune disorder triggered by ingestion of gluten, have been reported in IgA nephropathy. However, studies are inconsistent about this association. We aimed to evaluate the proposed link between IgA nephropathy and celiac disease or immune reactivity to gluten by conducting a comprehensive analysis of associated serologic markers in cohorts of well-characterized patients and controls. Study participants included patients with biopsy-proven IgA nephropathy (n = 99), unaffected controls of similar age, gender, and race (n = 96), and patients with biopsy-proven celiac disease (n = 30). All serum specimens were tested for IgG and IgA antibodies to native gliadin and deamidated gliadin, as well as IgA antibody to transglutaminase 2 (TG2). Anti-TG2 antibody-positive nephropathy patients and unaffected controls were subsequently tested for IgA anti-endomysial antibody and genotyped for celiac disease-associated HLA-DQ2 and -DQ8 alleles. In comparison to unaffected controls, there was not a statistically significant increase in IgA or IgG antibody reactivity to gliadin in individuals with IgA nephropathy. In addition, the levels of celiac disease-specific serologic markers, i.e., antibodies to deamidated gliadin and TG2, did not differ between IgA nephropathy patients and unaffected controls. Results of the additional anti-endomysial antibody testing and HLA genotyping were corroborative. The data from this case-control study do not reveal any evidence to suggest a significant role for celiac disease or immune reactivity to gluten in IgA nephropathy.

Sprue-like histology in patients with abdominal pain taking olmesartan compared with other angiotensin receptor blockers

Aims A severe syndrome characterised by life-threatening diarrhoea and severe sprue-like histology has been described in patients taking the angiotensin receptor blocker (ARB) olmesartan. It is unknown whether there are any histopathological changes in patients without severe diarrhoea exposed to this medication. It is also unknown whether other ARBs cause sprue-like histology. Methods Retrospective cohort study of patients with abdominal pain undergoing upper gastrointestinal endoscopy with duodenal biopsy who were taking ARBs. Patients taking olmesartan (n=20) and a non-olmesartan ARB (n=20) were compared with age and sex-matched controls. Histological features (classic sprue-like and other inflammatory changes) were analysed. Results No single histopathological finding was significantly more common in olmesartan-using patients than controls. However, 10 of 20 olmesartan patients had one or more sprue-like histological features compared with 4 of 20 age-matched and sex-matched controls not taking ARBs (p=0.10). Patients taking ARBs other than olmesartan were not more likely than controls to have one or more of these sprue-like histological features (9/20 vs. 12/20, p=0.34). Conclusions There were no statistically significant differences between olmesartan users with abdominal pain and controls for any single histopathological abnormality. However, there were trends towards significance for individual abnormalities as well as for a composite outcome of sprue-like changes. This raises the possibility that there is a spectrum of histological changes associated with olmesartan use.

Immunohistochemical and T-cell receptor gene rearrangement analyses as predictors of morbidity and mortality in refractory celiac disease.

Background: Classification of refractory celiac disease (RCD) is based on the presence or absence of monoclonal expansions of intraepithelial lymphocytes (IELs) with an aberrant immunophenotype. Goals: To investigate the contribution of IEL parameters toward mortality and morbidity in RCD. Study: IEL phenotype by immunohistochemistry and T-cell receptor (TCR) gene rearrangement by polymerase chain reaction were assessed in 73 RCD patients (type I=67, type II=6). Detection of a monoclonal TCR gene rearrangement and presence of <50% CD3+ CD8+ IELs were considered abnormal. Time to worsening of clinical symptoms and predictors of worsening were calculated by Kaplan-Meier and Cox proportional hazard analyses. Results: Fewer than 50% CD3+ CD8+ IELs were detected in 30 patients and monoclonal TCR rearrangements in 6. Three patients died and 40 suffered clinical worsening despite treatment. Estimated 5-year survival rates decreased from 100% in patients with >50% CD3+ CD8+ IELs and polyclonal TCR to 88% and 50% in patients with <50% CD3+ CD8+ IELs and monoclonal TCR, respectively. Clinical worsening was more frequent (100%) among patients harboring a monoclonal TCR gene rearrangement with <50% CD3+ CD8+ IELs. These patients also showed shorter median time to clinical worsening (11 mo) when compared to patients with <50% CD3+ CD8+ IELs alone (21 mo), polyclonal TCR (38 mo), or >50% CD3+ CD8+ IELs alone (66 mo). After adjusting for age and gender, only the presence of <50% CD3+ CD8+ IELs was associated with increased risk for clinical worsening despite negative celiac serologies (hazard ratio=4.879; 95% confidence interval, 1.785-13.336; P=0.002). Conclusions: Presence of <50% CD3+ CD8+ IELs is a risk factor for clinical worsening in RCD and combined with a monoclonal TCR gene rearrangement result is associated with increased mortality. IEL phenotype and TCR gene rearrangement analyses provide differential information regarding morbidity and mortality in RCD.

Hemolysis Interferes with the Detection of Anti–Tissue Transglutaminase Antibodies in Celiac Disease

Detection of anti–tissue transglutaminase (tTG)1 antibodies by the use of human recombinant or erythrocyte tTG-IgA–based ELISA assays is 1 of the preferred tests for diagnosing celiac disease (CD) (1). However, studies comparing different tTG kits have revealed variable sensitivities, raising concern in clinical practice(2). Erythrocytes (RBC) contain tTG(3). In patients, upon hemolysis, the endogenous RBC-tTG released may immunoprecipitate with anti-tTG antibodies and interfere with their detection. Newer anti–deamidated gliadin peptide (DGP)-IgA assays, however, should not be affected(4). To assess the effect of hemolysis on tTG-IgA titers, we used stored sera from 9 patients with biopsy-confirmed, active CD who gave informed consent for study participation. Samples were divided into 3 groups (n = 3, in each) according to the tTG-IgA concentrations after thawing [high titer (>185 U), intermediate titer (100–140 U), and borderline titer (20–50 U)]. A whole-blood sample from 1 tTG/DGP-seronegative patient, which contained 149 g/L of hemoglobin (HGB), was hemolyzed by freezing and thawing until >90% of cells were lysed, then serially diluted (1:2, 1:5, 1:10, 1:50, 1:100, 1:500) in PBS to obtain HGB concentrations of 67.1, 26.8, 13.4, 2.7, 1.3, and 0.27 g/L, respectively, and finally, added to each sample at a 1:1 ratio. For the tTG sequestration experiment, human recombinant tTG from Diarect AG was added for a final concentration of 0.04, 0.02, …

Clonal T cell receptor gene rearrangements in coeliac disease: implications for diagnosing refractory coeliac disease

Aims Refractory coeliac disease type II (RCDII), a rare complication of coeliac disease (CD) associated with high morbidity, requires identification of a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs) for diagnosis. However, data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII are limited. Methods We analysed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active CD, 172 CD on gluten-free diet (GFD), 33 RCDI, and three RCDII patients and 14 patients without CD. TCR-GR patterns were divided into clonal, polyclonal and prominent clonal peaks (PCPs) and these patterns were correlated with clinical and pathological features. Results Clonal TCR-GR products were detected in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with GFD. PCPs were observed in all disease phases (range 12%–33%). There was no significant difference in the TCR-GR patterns between the non-RCDII disease categories (p=0.39). A higher frequency of surface CD3(−) IELs was noted in cases with clonal TCR-GR, but the PCP pattern did not show associations with any clinical or pathological feature. Persistence of clonal or PCP pattern on repeat biopsy was seen for up to 2 years without evidence of RCDII. Conclusions Clonal TCR-GRs are not infrequent in cases lacking features of RCDII, while PCPs are frequent in all disease phases. TCR-GR results should be assessed in conjunction with immunophenotypic, histological and clinical findings for appropriate diagnosis and classification of RCD.

Su1445 Lack of Serologic Evidence for an Association Between Gluten Sensitivity and IgA Nephropathy

in the prevalence of esophageal dysplasia in patients with and without gluten-related disorders, the patients with Celiac Disease seem to develop dysplasia earlier (Long Rank p=0.01). Conclusions: Our results show an increased prevalence of gluten-related disorders in a cohort of patients with BE compared to the population referred to our center. Patients with gluten-related disorders may have a higher risk of accelerated development of dysplasia. Future studies are needed to confirm these findings in a larger group of patients.

Su1440 Histopathologic Outcomes in Olmesartan Related Enteropathy

Olmesartan-Associated Sprue: A French National Study Lysiane Marthey, Guillaume Cadiot, Philippe Seksik, Philippe Pouderoux, Joel Lacroute, Florence Skinazi, Bruno Mesnard, Jean Alain Chayvialle, Eric Lerebours, Anne Druez, David Parlier, Vered Abitbol, Michel Gompel, Matthieu Eoche, Eric Poncin, Roland Bobichon, Philippe Colardelle, Pauline Wils, Nadine Cerf Bensussan, Georgia Malamut, Franck Carbonnel