Publications by authors named "Arzu Ensari"

108 Publications

Gluten Induces Subtle Histological Changes in Duodenal Mucosa of Patients with Non-Coeliac Gluten Sensitivity: A Multicentre Study.

Nutrients 2022 Jun 15;14(12). Epub 2022 Jun 15.

Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN 55907, USA.

Histological changes induced by gluten in the duodenal mucosa of patients with non-coeliac gluten sensitivity (NCGS) are poorly defined. To evaluate the structural and inflammatory features of NCGS compared to controls and coeliac disease (CeD) with milder enteropathy (Marsh I-II). Well-oriented biopsies of 262 control cases with normal gastroscopy and histologic findings, 261 CeD, and 175 NCGS biopsies from 9 contributing countries were examined. Villus height (VH, in μm), crypt depth (CrD, in μm), villus-to-crypt ratios (VCR), IELs (intraepithelial lymphocytes/100 enterocytes), and other relevant histological, serologic, and demographic parameters were quantified. The median VH in NCGS was significantly shorter (600, IQR: 400-705) than controls (900, IQR: 667-1112) ( < 0.001). NCGS patients with Marsh I-II had similar VH and VCR to CeD [465 µm (IQR: 390-620) vs. 427 µm (IQR: 348-569, = 0·176)]. The VCR in NCGS with Marsh 0 was lower than controls ( < 0.001). The median IEL in NCGS with Marsh 0 was higher than controls (23.0 vs. 13.7, < 0.001). To distinguish Marsh 0 NCGS from controls, an IEL cut-off of 14 showed 79% sensitivity and 55% specificity. IEL densities in Marsh I-II NCGS and CeD groups were similar. : NCGS duodenal mucosa exhibits distinctive changes consistent with an intestinal response to luminal antigens, even at the Marsh 0 stage of villus architecture.
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http://dx.doi.org/10.3390/nu14122487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9230100PMC
June 2022

Histopathology of non-coeliac gluten sensitivity.

Virchows Arch 2022 Feb 11;480(2):315-322. Epub 2022 Jan 11.

Department of Pathology, Ankara University Medical School, Ankara, Turkey.

Diagnosis of non-coeliac gluten sensitivity (NCGS) remains still problematic due to the subjectiveness and lack of a specific biomarker. We aimed to compare NCGS duodenal mucosae with healthy individuals and Marsh type 1 coeliac disease (CD), to determine whether NCGS has characteristic histological features. A total of 44 healthy controls, 42 NCGS, and 44 type 1 CD patients were selected according to clinical, serological, and laboratory data. Duodenal biopsies were evaluated on H&E, CD, and CD117 for villus/crypt ratio, IEL counts/100 enterocytes, uneven distribution pattern with clusters of IELs in the villous epithelium, linear distribution of T lymphocytes in the basal lamina propria, and eosinophils and mast cells in the lamina propria. IEL counts were within normal range in controls (13 ± 7.65), normal or mildly increased in NCGS (24.7 ± 10.46), and increased in CD (58.79 ± 14.97) on CD3. The presence of uneven distribution pattern of IELs in the villous epithelium was significantly higher in NCGS (90.5%), in contrast to controls (27.3%) and CD (34.1%). The presence of linear distribution of T lymphocytes in the basal lamina propria (68.2%, 76.2%, 78.1%), eosinophil counts (6.85 ± 3.42, 6.21 ± 2.8, 7.62 ± 3.89), and mast cell counts (25.1 ± 5.1, 26 ± 2.9, 30.3 ± 4.4) was similar in controls, NCGS, and CD, respectively. In conclusion, duodenal mucosae in NCGS are characterized by preserved villous architecture, normal or mildly increased IELs with clusters, and eosinophils and mast cells within normal limits. We believe uneven distribution of IELs with clusters in the villous epithelium can be used as a supportive histopathological tool for NCGS in the right clinical setting.
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http://dx.doi.org/10.1007/s00428-021-03257-5DOI Listing
February 2022

Membranous Nephropathy with Lambda Light Chain Restriction: A Rare Form with Serum Negative and Tissue Positive PLA2R Ab.

Nephron 2022 22;146(4):377-380. Epub 2021 Dec 22.

Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Subepithelial polyclonal immunoglobulin deposits and >70% M-type phospholipase A2 receptor antibody positivity are typical findings in idiopathic MN. A 58-year-old female patient was admitted with clinical presentation of nephrotic syndrome. Autoimmune diseases, infections, and malignancies were ruled out after clinical and laboratory evaluations. Diagnostic work-up revealed serum PLA2R antibody negativity and diffuse thickening of glomerular capillary wall on biopsy, while glomerular capillary wall IgG, C3, and Lambda monotypic light chain deposition and PLA2R1 positivity were detected by immunofluorescence and immunohistochemical examination, respectively. Following prednisolone treatment, creatinine and proteinuria were markedly regressed. The MN cases with a light chain deposits are rare and experience regarding their treatment are insufficient.
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http://dx.doi.org/10.1159/000520943DOI Listing
July 2022

What's in a Name? Michael N. Marsh, BTh, DPhil, DM, DSc, FRCP*

Authors:
Arzu Ensari

Turk Patoloji Derg 2021 ;37(3):193-195

Ankara University School of Medicine. Department of Pathology, ANKARA, TURKEY.

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http://dx.doi.org/10.5146/tjpath.2021.01553DOI Listing
March 2022

Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts.

Gut 2021 05 2;70(5):876-883. Epub 2020 Nov 2.

Academic Unit of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK

Objective: We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients.

Design: The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD.

Results: Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively.

Conclusion: Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD.
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http://dx.doi.org/10.1136/gutjnl-2020-320913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040155PMC
May 2021

Gastric and small intestinal traditional serrated adenomas: a detailed morphologic and immunohistochemical analysis.

Turk J Gastroenterol 2020 06;31(6):441-450

Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.

Background/aims: Traditional serrated adenomas (TSAs), despite their low incidence in colorectum, may originate in other parts of the gastrointestinal (GI) tract, including stomach and small intestine. Malignant transformation for upper GI TSAs has recently been reported in the literature. Here, we present a series of gastric and small intestinal TSAs with the aim to characterize their morphologic and immunophenotypic features as well as their neoplastic potential in a compartmental manner using digitalized images.

Materials And Methods: The study comprised 12 GI polyps with TSA features-5 gastric and 7 small intestinal. The extent of the characteristic features of TSA, including eosinophilic cells, ectopic crypt foci (ECF), slit-like serration, foveolar epithelium, goblet cells, together with dysplastic-carcinomatous foci were assessed on digitalized H-E images and were used as reference for immunohistochemical analysis.

Results: All polyps in the cohort contained eosinophilic cells as the most extensive morphologic feature followed by ECF and slit-like serration in decreasing order. Serrated dysplasia was more common in gastric polyps, which more frequently showed neoplastic progression compared with the intestinal ones. CK20 was the most widely expressed marker with a preference to eosinophilic cells while ECFs were mostly negative. Ki67 showed the opposite pattern of CK20. MUC6 and MUC2 were selectively expressed in the basal zone and goblet cells, respectively.

Conclusion: Our results showed that the presence of eosinophilic cells with pencillate nuclei commonly accompanied by ECF and slit-like serration are the defining features of gastric and small intestinal TSAs. They frequently harbor neoplastic foci, particularly in gastric location where serrated dysplasia seems to be more common.
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http://dx.doi.org/10.5152/tjg.2020.19931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433998PMC
June 2020

Duodenal bulb biopsy in the diagnostic work-up of coeliac disease.

Virchows Arch 2020 Oct 13;477(4):507-515. Epub 2020 May 13.

Department of Pathology, Ankara University Medical School, Sihhiye, 06100, Ankara, Turkey.

Coeliac disease (CD) is an autoimmune enteropathy which can present with patchy mucosal lesions. The aim of the present study is to investigate the significance of duodenal bulb biopsy in the diagnostic work-up of CD in both pediatric and adult patients, and to highlight the key points for pathologists. D1 (duodenal bulb) and D2 (distal duodenum) biopsies of 153 newly diagnosed serology-positive CD patients were evaluated for villous/crypt ratio and intraepithelial lymphocyte (IEL) counts on CD3-stained slides and were classified according to Marsh. Mucosal pathology was patchy in 15% (13% only D1 and 2% only D2) of patients, and 85% of patients had diffuse mucosal pathology involving both D1 and D2 biopsies which showed concordant histology in 60% and discordant in 25% of the cases. Though majority of the patients (75%) with only D1 involvement were pediatric cases, no significant difference was found between pediatric and adult patients when all cases were considered (17 vs 14%). Our results clearly indicate that without D1 sampling, diagnosis of CD would have been missed in a significant number of cases (13%), thereby highlighting the importance of taking duodenal biopsies from multiple sites in the diagnostic work-up of CD. We, therefore, conclude that every biopsy piece from both D1 and D2 should be carefully evaluated for the whole spectrum of mucosal changes caused by gluten ingestion and classified using a scheme based on Marsh to allow recognition of mild lesions.
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http://dx.doi.org/10.1007/s00428-020-02832-6DOI Listing
October 2020

Novel mutations of SAR1B gene in four children with chylomicron retention disease.

J Clin Lipidol 2019 Jul - Aug;13(4):554-562. Epub 2019 May 30.

Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. Electronic address:

Background: Intestinal lipid malabsorption, resulting from an impaired formation or secretion of chylomicrons and associated with severe hypobetalipoproteinemia (HBL), may be due to biallelic mutations in APOB (homozygous FHBL type-1), MTTP (abetalipoproteinemia), or SAR1B (chylomicron retention disease).

Objective: We investigated four children, each born from consanguineous parents, presenting with steatorrhea, malnutrition, accumulation of lipids in enterocytes, and severe hypocholesterolemia with an apparent recessive transmission.

Methods: We sequenced a panel of genes whose variants may be associated with HBL.

Results: Case 1, a 9-month-old male, was found to be homozygous for a SAR1B variant (c.49 C>T), predicted to encode a truncated Sar1b protein devoid of function (p.Gln17*). Case 2, a 4-year-old male, was found to be homozygous for a SAR1B missense variant [c.409 G>C, p.(Asp137His)], which affects a highly conserved residue close to the Sar1b guanosine recognition site. Case 3, a 6-year-old male, was found to be homozygous for an ∼6 kb deletion of the SAR1B gene, which eliminates exon 2; this deletion causes the loss of the ATG translation initiation codon in the SAR1B mRNA. The same homozygous mutation was found in an 11-month-old child (case 4) who was related to case 3.

Conclusions: We report 4 children with intestinal lipid malabsorption were found to have chylomicron retention disease due to 3 novel variants in the SAR1B gene.
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http://dx.doi.org/10.1016/j.jacl.2019.05.013DOI Listing
June 2020

Diagnosing celiac disease: A critical overview.

Turk J Gastroenterol 2019 May;30(5):389-397

Wolfson College, University of Oxford, Oxford, UK.

The diagnosis of celiac disease (CD) no longer rests on a malabsorptive state or severe mucosal lesions. For the present, diagnosis will always require the gold-standard of a biopsy, interpreted through its progressive phases (Marsh classification). Marsh classification articulated the immunopathological spectrum of gluten-induced mucosal changes in association with the recognition of innate (Marsh I infiltration) and T cell-based adaptive (Marsh II, and the surface re-organisation typifying Marsh III lesions) responses. Through the Marsh classification the diagnostic goalposts were considerably widened thus, over its time-course, permitting countless patients to begin a gluten-free diet but who, on previous criteria, would have been denied such vital treatment. The revisions of this classification failed to provide additional insight in the interpretation of mucosal pathology. Morever, the subclassification of Marsh 3 imposed an enormous amount of extra work on pathologists with no aid in diagnosis, treatment, or prognosis. Therefore, it should now be apparent that if gastroenterologists ignore these sub-classifications in clinical decision-making, then on that basis alone, there is no need whatsoever for pathologists to persist in reporting them. Since new treatments are under critical assessment, we might have to consider use of some other higher level histological techniques sensitive enough to detect the changes sought. A promising alternative would be to hear more voices from imaginative histopathologists or morphologists together with some more insightful approaches, involving molecular-based techniques and stem cell research may be to evaluate mucosal pathology in CD.
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http://dx.doi.org/10.5152/tjg.2018.18635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6505646PMC
May 2019

Vascular endothelial growth factor, endostatin levels and clinical features among patients with ulcerative colitis and irritable bowel syndrome and among healthy controls: a cross-sectional analytical study.

Sao Paulo Med J 2018 Nov-Dec;136(6):543-550

MD. Associate Professor, Department of Gastroenterology, Gazi Yaşargil Training And Research Hospital, Diyarbakır, Turkey.

Background: Increased angiogenetic activity in inflammatory bowel disease (IBD) has been shown in previous studies. The aim of this study was to evaluate the relationship of serum vascular endothelial growth factor (VEGF) and endostatin levels with clinical features and mucosal expression in patients with ulcerative colitis (UC).

Design And Setting: Cross-sectional analytical study conducted in a tertiary-level public hospital.

Methods: Serum VEGF and endostatin levels were determined in 82 individuals: 39 with UC, 28 with irritable bowel syndrome (IBS) and 15 healthy controls (HCs), using enzyme-linked immunosorbent assays (ELISA). VEGF and endostatin expressions were studied using immunohistochemistry (IHC).

Results: Mean serum VEGF and endostatin levels were significantly higher in patients with UC than in patients with IBS and in HCs (511.9 ± 377.5 pg/ml, 305.0 ± 121.42 pg/ml and 36.1 ± 40.6 pg/ml; P = 0.001 for VEGF; and 155.50 ± 59.8 ng/ml, 116.9 ± 23.8 ng/ml and 102.2 ± 22.4 ng/ml; P < 0.001 for endostatin, respectively). There was a positive correlation between serum VEGF and endostatin levels (r = 0.422; P < 0.01). Mean H-scores for VEGF expression were higher in the active UC group than in the inactive UC and IBS groups, in the stroma, endothelium and epithelium. Mean H-scores for endostatin expression were higher in the active UC group than in the inactive UC and IBS groups, in the stroma and endothelium. There was no endostatin expression in the epithelium.

Conclusion: Increased endostatin appears to be a defensive reaction to increased VEGF in patients with UC.
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http://dx.doi.org/10.1590/1516-3180.2018.0274161118DOI Listing
June 2019

Tumor-associated Macrophages and Neuroendocrine Differentiation Decrease the Efficacy of Bevacizumab Plus Chemotherapy in Patients With Advanced Colorectal Cancer.

Clin Colorectal Cancer 2019 06 27;18(2):e244-e250. Epub 2018 Dec 27.

Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey. Electronic address:

Background: In the present study, we investigated the prognostic and predictive role of neuroendocrine differentiation (NED) and tumor-associated macrophage (TAM) infiltration in tumor tissue from patients with advanced colorectal cancer who had received bevacizumab plus chemotherapy.

Patients And Methods: A total of 123 consecutive patients with advanced colorectal cancer who had received bevacizumab plus irinotecan/oxaliplatin-based combination chemotherapy were included in the present study. In addition to the clinicopathologic parameters, the presence of NED and the level of TAM infiltration were studied as covariates for survival analysis.

Results: The median patient age was 57 years (range, 30-76 years). The chemotherapy backbone was FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) for 75% of the patients. Univariate analysis showed that only NED and TAM infiltration were significant predictive factors for progression-free survival. Left-sided tumors and low TAM infiltration were favorable factors for overall survival on univariate analysis. However, the TAM level was the only independent prognostic factor for overall survival (hazard ratio, 0.301; 95% confidence interval, 0.102-0.892).

Conclusion: Our results suggest that increased TAM infiltration in tumor tissue and NED could decrease the efficacy of bevacizumab plus combination chemotherapy in patients with advanced colorectal cancer. TAM infiltration in the tumor tissue could be used as a biomarker in patients with advanced colorectal cancer receiving bevacizumab plus chemotherapy.
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http://dx.doi.org/10.1016/j.clcc.2018.12.004DOI Listing
June 2019

Morphologic spectrum of gluten-related disorders: how far to go?

Virchows Arch 2019 05 19;474(5):641-642. Epub 2019 Jan 19.

Department of Pathology, Faculty of Medicine, Ankara University, Ankara, Turkey.

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http://dx.doi.org/10.1007/s00428-019-02522-yDOI Listing
May 2019

Discriminant value of IEL counts and distribution pattern through the spectrum of gluten sensitivity: a simple diagnostic approach.

Virchows Arch 2018 Nov 9;473(5):551-558. Epub 2018 Aug 9.

Department of Pathology, Ankara University Faculty of Medicine, Sihhiye, 06100, Ankara, Turkey.

Intraepithelial lymphocytosis (IELosis) with or without villous abnormality is a characteristic feature of gluten sensitivity (GS) including celiac disease (CD) and non-celiac-GS, although various conditions may also be associated with IELosis. In order to distinguish GS from the other causes of IELosis, a threshold for IEL counts is necessary. We aimed to determine a cut-off value for IELs and monitor its value in the spectrum of GS in a large cohort. For this purpose, the duodenal biopsies from four groups of individuals including Types 1 (n = 88) and 3 (n = 92) CD, non-CD IELosis (n = 112), and control (n = 82) cases, all strictly defined by their clinical, laboratory, and serologic features, were evaluated. The number of IELs/100 enterocytes and their distribution pattern on H&E- and CD3-immunostained sections were assessed for each group. Kruskal-Wallis test and ROC curve analysis for discriminant value were employed for statistics. The IEL counts showed an increasing trend through the spectrum of mucosal pathology including controls (12.06; 21.40), non-CD IELosis (28.62; 39.46), Type 1 CD (49.27; 60.15), and Type 3 CD (58.53; 71.74) both on H&E- and CD3-immunostained sections, respectively (p < 0.001). ROC analysis revealed 20.5 on H&E and 28.5 on CD3 as the IEL cut-off values with a sensitivity of 95.9 and 87.7% and a specificity of 98.8% and 93.9%, respectively, for controls. IELs showed a diffuse distribution pattern per biopsy piece and per villus (90.9%, 100%, respectively) in nearly all of Type 1 CD cases (p < 0.001). An IEL cut-off value of 20.5 on H&E together with a diffuse distribution pattern seem to be the most discriminant features for the diagnosis of CD, even for the milder forms of the disease.
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http://dx.doi.org/10.1007/s00428-018-2430-1DOI Listing
November 2018

Exploring the villus.

Gastroenterol Hepatol Bed Bench 2018 ;11(3):181-190

Luton & Dunstable University Hospitals NHS Trust, Wolfson College, University of Oxford, UK.

The small intestinal villus and its associated epithelium includes enterocytes as the main cell type and differentiated goblet and argentaffin cells, while the invaginated crypt epithelium is the site of cell division and hence the origin of all epithelial components. Enterocytes form a cohesive monolayer which acts both as a permeability barrier between lumen and the interior, and an important gateway for nutrient digestion, absorption and transport. Differentiation and polarisation of enterocytes depends on cytoskeletal proteins that control cell shape and maintain functionally specialised membrane domains; extracellular matrix (ECM) receptors; channels and transporters regulating ion/solute transfer across the cell. The mesenchymally-derived basement membrane dynamically controls morphogenesis, cell differentiation and polarity, while also providing the structural basis for villi, crypts and the microvasculature of the lamina propria so that tissue morphology, crucially, is preserved in the absence of epithelium. Mucosal re-organisation requires immense cooperation between all elements within the lamina, including marked revisions of the microvasculature and extensive alterations to all basement membranes providing support for endodermal and mesenchymal components. In this context, subepithelial myofibroblasts fulfil important regulatory activities in terms of tissue morphogenesis; remodelling; control of epithelial cell development, polarity and functional attributes; and an intimate involvement in repair, inflammation and fibrosis. This paper reviews the main structural and functional aspects of the villus, including the epithelium and its outer glycocalyx and microvillous border; and subjacent to the epithelium, the basement membrane with its attached web of myo-fibroblasts together with the lamina propria core of the villi, and its microvasculature and lacteals. Finally, some comments on the rapidity with which the overall structure of the villi changes in their response to both external, and internal, influences.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040026PMC
January 2018

Coeliac biopsies: numbers are valid, alphabets not.

Gut 2018 11 20;67(11):2069-2070. Epub 2017 Nov 20.

Department of Gastroenterology, Luton and Dunstable University Hospital, Luton, UK.

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http://dx.doi.org/10.1136/gutjnl-2017-315517DOI Listing
November 2018

Non-Diabetic Kidney Disease in Type 2 Diabetic Patients: Prevalence, Clinical Predictors and Outcomes.

Kidney Blood Press Res 2017 1;42(5):886-893. Epub 2017 Nov 1.

Ankara University School of Medicine, Department of Nephrology, Ankara, Turkey.

Background/aims: Diabetic kidney disease (DKD) is one of the most frequent microvascular complications of diabetes and is the leading cause of end-stage kidney disease worldwide. In patients with diabetes, non-diabetic kidney disease (NDKD) can also occur. NDKD can be either alone or superimposed with the DKD. In this study, we aimed to investigate the utility of kidney biopsy in patients with type 2 diabetes mellitus (T2DM) and the predictability of diagnosing DKD versus NDKD from clinical and laboratory data. We also evaluated the prevalence and etiology of NDKD in patients with T2DM.

Methods: We retrospectively reviewed type 2 diabetic patients who had kidney biopsy in the last 10 years for diagnosing possible NDKD in our center. In all patients kidney biopsies were performed because of atypical clinical features and biopsy samples were examined by light and immunofluorescence microscopy. Clinical parameters, laboratory workup and office blood pressures were recorded for each patient at the time of biopsy.

Results: Eight patients were excluded due to missing data. A total of 48 patients (female/male: 26/22 and mean age: 59±8 years) were included in the study. According to the biopsy findings, 24 (50%) patients had NDKD alone, 20 (41.7%) had DKD alone and 4 (8.3%) had coexisting DKD and NDKD. The most common NDKD diagnoses were membranous nephropathy (29.2%), tubulointerstitial nephritis (20.8%) and IgA nephropathy (12.5%). There were no significant differences in three groups with respect to the duration of diabetes, proteinuria, hematuria and glycated hemoglobin A1c levels. Diabetic retinopathy (DR) was the most significant finding, which was associated with DKD. Positive and negative predictive values of DR for DKD were 88 and 81%, respectively.

Conclusion: This study demonstrated a high prevalence of NDKD in patients with T2DM. The absence of DR strongly predicted NDKD. Clinical decision alone can lead to wrong diagnosis and delay in appropriate therapy. Clinicians should consider the kidney biopsy more liberally when there is uncertainty on the exact etiology of the kidney disease. However, prospective multicenter studies are needed to clarify the prognosis and outcomes of patients with diabetics.
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http://dx.doi.org/10.1159/000484538DOI Listing
August 2018

Multiple Presentations of LRBA Deficiency: a Single-Center Experience.

J Clin Immunol 2017 Nov 27;37(8):790-800. Epub 2017 Sep 27.

Department of Pediatric Allergy and Immunology, Ankara University School of Medicine, Cebeci, 06590, Ankara, Turkey.

Introduction: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency categorized as common variable immunodeficiency associated with autoimmune manifestations and inflammatory bowel diseases; however, the clinical spectrum has been extended. Here, we present our cohort of Turkish LRBA-deficient patients from a single center, demonstrating a diversity of clinical manifestations.

Method: Seven affected individuals from five families were assessed retrospectively in this study.

Results: Of the seven patients with LRBA deficiency, four had homozygous, and two had compound heterozygous mutations. One patient remained disease free until the last follow-up (age 17 years). The most common clinical manifestations of the six symptomatic patients were organomegaly (6/6), autoimmunity (6/6), and chronic diarrhea (5/6). Recurrent infectious episodes were observed in three patients. None of the patients had hypogammaglobulinemia at presentation. B cell subpopulation analysis revealed low numbers of switched-memory B cell numbers in two of the four tested patients. During the disease course, three of the patients died, two of them underwent successful hematopoietic stem cell transplantation (HSCT) from matched sibling donors, and one is under abatacept therapy.

Conclusion: LRBA defects should always be kept in mind as a differential diagnosis for patients with autoimmune disease affecting multiple organs, chronic diarrhea, and organomegalies. In our experience, early HSCT is a life-saving therapeutic strategy.
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http://dx.doi.org/10.1007/s10875-017-0446-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086713PMC
November 2017

ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation.

Gut 2017 12 11;66(12):2080-2086. Epub 2017 Sep 11.

Departments of Gastroenterology and Pathology, Grigore T. Popa University of Medicine and Pharmacy, Iasi, Romania.

Objectives: Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive 'normal' IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens.

Design: The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected.

Results: The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2-88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion.

Conclusion: Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose-response by IEL to environmental (gluten) antigenic influence.
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http://dx.doi.org/10.1136/gutjnl-2017-314297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749338PMC
December 2017

Newcomers in paediatric GI pathology: childhood enteropathies including very early onset monogenic IBD.

Virchows Arch 2018 Jan 17;472(1):111-123. Epub 2017 Jul 17.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Perelman School of Medicine at The University of Pennsylvania, 3401 Civic Center Boulevard, 5 NW26, Philadelphia, PA, 19104, USA.

Childhood enteropathies are a group of diseases causing severe chronic (>2-3 weeks) diarrhoea often starting in the first week of life with the potential for fatal complications for the affected infant. Early identification and accurate classification of childhood enteropathies are, therefore, crucial for making treatment decisions to prevent life-threatening complications. Childhood enteropathies are classified into four groups based on the underlying pathology: (i) conditions related to defective digestion, absorption and transport of nutrients and electrolytes; (ii) disorders related to enterocyte differentiation and polarization; (iii) defects of enteroendocrine cell differentiation; and (iv) disorders associated with defective modulation of intestinal immune response. While the intestinal mucosa is usually normal in enteropathies related to congenital transport or enzyme deficiencies, the intestinal biopsy in other disorders may reveal a wide range of abnormalities varying from normal villous architecture to villous atrophy and/or inflammation, or features specific to the underlying disorder including epithelial abnormalities, lipid vacuolization in the enterocytes, absence of plasma cells, lymphangiectasia, microorganisms, and mucosal eosinophilic or histiocytic infiltration. This review intends to provide an update on small intestinal biopsy findings in childhood enteropathies, the "newcomers", including very early onset monogenic inflammatory bowel disease (IBD), in particular, for the practicing pathologist.
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http://dx.doi.org/10.1007/s00428-017-2197-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6171108PMC
January 2018

Kidney biopsy in AA amyloidosis: impact of histopathology on prognosis.

Amyloid 2017 Sep 7;24(3):176-182. Epub 2017 Jul 7.

a Department of Nephrology , Ankara University School of Medicine , Ankara , Turkey.

In AA amyloidosis, while kidney biopsy is widely considered for diagnosis by clinicians, there is no evidence that the detailed investigation of renal histopathology can be utilized for the prognosis and clinical outcomes. In this study, we aimed to obtain whether histopathologic findings in kidney biopsy of AA amyloidosis might have prognostic and clinical value. This is a retrospective cohort study that included 38 patients who were diagnosed with AA amyloidosis by kidney biopsy between 2005 and 2013.The kidney biopsy specimens of patients were evaluated and graded for several characteristics of histopathological lesions and their relationship with renal outcomes. Segmental amyloid deposition in the kidney biopsy was seen in 29%, global amyloid deposition in 71, diffuse involvement of glomeruli in 84.2%, focal involvement in 7%, glomerular enlargement in 53%, tubular atrophy in 75% and interstitial fibrosis in 78% of patients. Histopathologically, glomerular enlargement, interstitial fibrosis, tubular atrophy, interstitial inflammation and global amyloid deposition were significantly associated with lower estimated glomerular filtration rate (eGFR) (p = .02, p < .001, p = .001, p = .009, p = .002, respectively) in univariate analysis. In multivariate analysis, tubular atrophy was the only predictor of eGFR (p = .019 B = -20.573). In the follow-up at an average of 27 months, 18 patients developed end-stage renal disease (ESRD). Among them, global amyloid deposition was the only risk factor for the development of ESRD (p = .01, OR = 18.750, %95 CI= 2.021-173.942). This is the first study showing that the histopathological findings in kidney biopsy of AA amyloidosis might have a prognostic and clinical value for renal outcomes.
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http://dx.doi.org/10.1080/13506129.2017.1350158DOI Listing
September 2017

Expression of CD44 variant 6 and its prognostic value in benign and malignant endometrial tissue.

Arch Gynecol Obstet 2017 Aug 15;296(2):313-318. Epub 2017 Jun 15.

Department of Pathology, Ankara University School of Medicine, Ankara, Turkey.

Purpose: CD44 expression in both the early and metastatic phases of many epithelial and non-epithelial cancers is strongly prognostic. The objective of the study is to evaluate whether there is any relationship between the expression of CDD44v6 and endometrial cancer (EC) staging and prognosis.

Methods: This retrospective study included 60 EC patients for whom surgical staging was performed between 2000 and 2006. Twenty-eight randomly selected patients with normal endometria served as the control group. We immunohistochemically evaluated membranous and cytoplasmic CD44v6 staining in tissue paraffin blocks. The results were graded as positive or negative.

Results: Membranous staining in both advanced and early stage EC patients was significantly higher than that in the control group (p = 0.002). The extent of either membranous or cytoplasmic staining in both advanced- and early stage patients did not differ significantly by age, tumor grade, stage, extent of myometrial invasion, lymph node involvement, cytology, adnexal involvement, or omental spreading. In advanced-stage patients, neither papillary serous not clear cell cancers exhibited cytoplasmic staining.

Conclusions: CD44v6 membranous staining can be useful for differentiating malignant from benign endometrial tissue. However, staining is not associated with EC staging or prognosis.
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http://dx.doi.org/10.1007/s00404-017-4430-9DOI Listing
August 2017

Bone mineral density and growth in children with coeliac disease on a gluten free-diet.

Turk J Med Sci 2016 Dec 20;46(6):1816-1821. Epub 2016 Dec 20.

Department of Pediatric Gastroenterology, Hepatology and Nutrition, Faculty of Medicine, Ankara University, Ankara, Turkey.

Background/aim: To evaluate changes in growth and bone metabolism during consumption of a gluten-free diet (GFD) in children with coeliac disease (CD).

Materials And Methods: Thirty-seven children with CD (mean age of 8.8 ± 4.6 years, 21 girls) were enrolled. Anthropometric measurements, bone mineral density (BMD) in lumbar 2-4 vertebrae, and serum alkaline phosphatase, calcium, and phosphorus levels at diagnosis and at follow-up were recorded.

Results: The mean follow-up period was 3.5 ± 2.3 years. The BMD of patients was significantly lower than that of control subjects at the time of diagnosis but not after 1 year of the GFD. Incidence of low BMD with respect to z-scores for chronological age (CA) was significantly higher than z-scores for height age (HA) (P = 0.006). At the first year of GFD, BMD, BMD z-score, height-for-age z-scores, and weight-for-age z-scores were significantly increased compared with the baseline, but not after 1 year of the GFD.

Conclusion: In CD, the first year of GFD is important in weight gain, linear growth, and improvement of BMD. A considerable relation of low BMD in children with CD, with respect to z-scores for CA, may be a result of misinterpretation of low BMD due to short stature.
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http://dx.doi.org/10.3906/sag-1508-52DOI Listing
December 2016

Classification chaos in coeliac disease: Does it really matter?

Pathol Res Pract 2016 Dec 3;212(12):1174-1178. Epub 2016 Sep 3.

Departments of Pathology, Ankara University Medical School, 06100, Sıhhıye, Ankara, Turkey. Electronic address:

The spectrum of mucosal pathology in coeliac disease (CD), initially defined by Marsh in 1992 has been subjected to several modifications in the following years by Oberhuber, then by Corazza and Villanaci, and finally by Ensari. The present study, aimed to end the ongoing confusion regarding the classification of mucosal pathology in CD by applying all the classifications proposed so far on a large series of cases. A total of 270 duodenal biopsies taken from the distal duodenum of patients with a diagnosis of CD were included in the study. All biopsies were classified according to Marsh, Oberhuber, Corazza Villanaci, and Ensari classification schemes. For statistical analyses cases were divided into three groups: Group 1 included type 1 lesions in Marsh, Ensari, and Oberhuber and grade A in Corazza Villanaci classifications. Group 2 comprised of type 2 lesions in Marsh and Ensari classifications together with type2, type 3a and 3b lesions in Oberhuber classification and grade B1 lesions in Corazza Villanaci classification. Group 3 included type 3 lesions in Marsh and Ensari classifications, and type 3c lesions in Oberhuber, and grade B2 lesions in Corazza Villanaci classifications. The kappa value was 1.00 (excellent) for group 1, 0.53 (fair) for group 2 and 0.78 (excellent) for group 3 (p<0.0001). These results suggest that any of the above classification system would serve similar purposes in the diagnosis of CD. Therefore, it is advisable that the pathologist should use the simplest reliable scheme.
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http://dx.doi.org/10.1016/j.prp.2016.08.012DOI Listing
December 2016

From RNA isolation to microarray analysis: Comparison of methods in FFPE tissues.

Pathol Res Pract 2016 Aug 12;212(8):678-85. Epub 2016 Feb 12.

Ankara University, Biotechnology Institute, Ankara, Turkey. Electronic address:

Background: Genome-wide gene expression profiling analysis of FFPE tissue samples is indispensable for cancer research and provides the opportunity to evaluate links between molecular and clinical information, however, working with FFPE samples is challenging due to extensive cross-linking, fragmentation and limited quantities of nucleic acid. Thus, processing of FFPE tissue samples from RNA extraction to microarray analysis still needs optimization.

Materials And Methods: In this study, a modified deparaffinization protocol was conducted prior to RNA isolation. Trizol, Qiagen RNeasy FFPE and Arcturus PicoPure RNA Isolation kits were used in parallel to compare their impact on RNA isolation. We also evaluated the effect of two different cRNA/cDNA preparation and labeling protocols with two different array platforms (Affymetrix Human Genome U133 Plus 2.0 and U133_X3P) on the percentage of present calls.

Results: Our optimization study shows that the Qiagen RNeasy FFPE kit with modified deparaffinization step gives better results (RNA quantity and quality) than the other two isolation kits. The Ribo-SPIA protocol gave a significantly higher percentage of present calls than the 3' IVT cDNA amplification and labeling system. However, no significant differences were found between the two array platforms.

Conclusion: Our study paves the way for future high-throughput transcriptional analysis by optimizing FFPE tissue sample processing from RNA isolation to microarray analysis.
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http://dx.doi.org/10.1016/j.prp.2015.11.008DOI Listing
August 2016

Coeliac disease: to classify or not to classify - that is the question!

Authors:
Arzu Ensari

Gastroenterol Hepatol Bed Bench 2016 ;9(2):73-4

Department of Pathology, Ankara University Medical School, Sihhiye 06100, Ankara, Turkey.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833843PMC
April 2016

A Clinical Approach to a Child with Hypoalbuminemia and Lymphopenia.

J Clin Immunol 2016 05 30;36(4):370-3. Epub 2016 Mar 30.

Department of Pediatric Immunology, Ankara University Faculty of Medicine, 06590, Cebeci, Ankara, Turkey.

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http://dx.doi.org/10.1007/s10875-016-0274-5DOI Listing
May 2016

Optimization of gene expression microarray protocol for formalin-fixed paraffin-embedded tissues.

Genom Data 2016 Mar 6;7:303-6. Epub 2016 Feb 6.

Ankara University, Biotechnology Institute, Ankara, Turkey.

Formalin-fixed paraffin-embedded (FFPE) tissue is a widely available clinical specimen for retrospective studies. The possibility of long-term clinical follow-up of FFPE samples makes them a valuable source to evaluate links between molecular and clinical information. Working with FFPE samples in the molecular research area, especially using high-throughput molecular techniques such as microarray gene expression profiling, has come into prominence. Because of the harmful effects of formalin fixation process such as degradation of nucleic acids, cross-linking with proteins, and chemical modifications on DNA and RNA, there are some limitations in gene expression profiling studies using FFPE samples. To date many studies have been conducted to evaluate gene expression profiling using microarrays (Thomas et al., Thomas et al. (2013) [1]; Scicchitano et al., Scicchitano et al. (2006) [2]; Frank et al., Frank et al. (2007) [3]; Fedorowicz et al., Fedorowicz et al. (2009) [4]). However, there is still no generally accepted, efficient and standardized procedure for microarray analysis of FFPE samples. This paper describes the microarray data presented in our recently accepted to be published article showing a standard protocol from deparaffinization of FFPE tissue sections and RNA extraction to microarray gene expression analysis. Here we represent our data in detail, deposited in the gene expression omnibus (GEO) database with the accession number GSE73883. Four combinations of two different cRNA/cDNA preparation and labeling protocols with two different array platforms (Affymetrix Human Genome U133 Plus 2.0 and U133_X3P) were evaluated to determine which combination gives the best percentage of present call. The study presents a dataset for comparative analysis which has a potential in terms of providing a robust protocol for gene expression profiling with FFPE tissue samples.
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http://dx.doi.org/10.1016/j.gdata.2016.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778669PMC
March 2016

Anti-VEGF-related thrombotic microangiopathy in a child presenting with nephrotic syndrome.

Pediatr Nephrol 2016 Jun 29;31(6):1029-32. Epub 2016 Feb 29.

Department of Pediatrics, Division of Pediatric Nephrology, Ankara University School of Medicine, Ankara, Turkey.

Background: Targeting the vascular endothelial growth factor (VEGF) signaling pathway has become an important approach to current cancer therapy. Anti-VEGF therapy-related renal adverse effects may present as hypertension, non-nephrotic proteinuria, and rarely as nephrotic syndrome (NS) and acute kidney injury.

Case-diagnosis/treatment: In this report, we present a 15-year-old boy who had developed nephrotic syndrome and thrombotic microangiopathy 26 months after administration of anti-VEGF therapy. Treatment was discontinued and nephrotic syndrome remitted spontaneously within 3 months.

Conclusions: Nephrologists should be aware of the side effects of anti-VEGF therapy. Early diagnosis and prompt management with withdrawal of the agents will result in spontaneous remission.
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http://dx.doi.org/10.1007/s00467-016-3355-zDOI Listing
June 2016

Change of Helicobacter pylori prevalence in a decade among children undergoing endoscopy.

Turk J Pediatr 2016 ;58(6):579-582

Ankara University Faculy of Medicine, Pediatric Gastroenterology, Ankara, Turkey.

Our aim was to investigate the trend of H. pylori infection among children during the last decade by a retrospective analysis. Reports of children in whom esophago-gastroduodenoscopy was performed at our institution during two periods 2002-2003 and 2012-2013 were seperated into Group I and Group II, respectively. Pathology reports were investigated for gastritis, atrophy and H. pylori presence. A total of 380 children, 131 in Group I and 249 in Goup II were recruited in the study. H. pylori postivity was found to be higher in Group I (% 48.1 and % 23.1, respectively, p < 0.001). Gastritis and atrophy were associated with H. pylori and both were more prevalent in Group I (p < 0.001). Our study demonstrates that H. pylori prevalence is decreasing in a pediatric population undergoing EGD in Ankara. This is the most recent study regarding pediatric H. pylori prevalence change in Turkey that we know of.
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http://dx.doi.org/10.24953/turkjped.2016.06.002DOI Listing
January 2016

Intractable colitis associated with chronic granulomatous disease in a young girl.

Turk J Pediatr 2015 Mar-Apr;57(2):189-91

Division of Pediatric Gastroenterology, Department of Pediatrics, Ankara University Faculty of Medicine, Ankara, Turkey.

Chronic granulomatous disease (CGD) is an autosomal recessive or X-linked disorder caused by NADPH oxidase deficiency leading to an impaired ability of reactive superoxide anion and metabolite formation and recurring severe bacterial and fungal infections, with a high mortality rate. Diarrhea, colitis, ileus, perirectal abscess formation and anal fissures are reported gastrointestinal findings in these patients. We report a case of intractable colitis associated with CGD in a young girl.
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August 2016
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