COSA NON È CELIACHIA ( uno sguardo obliquo )
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1 COSA NON È CELIACHIA ( uno sguardo obliquo ) Gino Roberto Corazza I Clinica Medica Fondazione IRCCS Policlinico San Matteo Università di Pavia
2 HOLY PAPERS OF COELIAC DISEASE Gut 2012 Gut 2014 JPGN 2012
3 COELIAC RELATED TERMS: CONSENSUS OR DISSENSUS? some points can be made clearer what at present is undefined still awaits a definition Di Sabatino & Corazza, Gut 2013 Oslo has hardly promoted a wider, definitional lucidity neither, crucially, has it pushed forward the ʺcoeliac conceptʺ intention of the Oslo group to provide uniform definition has not been achieved if the ESPGHAN criteria are also taken into account confusion about terminology continues Mäki, Nat Rev Gastroenterol Hepatol 2012 Marsh, Gut 2013
4 NEW ESPGHAN GUIDELINES a multicenter prospective trial in 707 pts ESPGHAN criteria PPV > 99% in symptomatic pediatric pts > 50% of children and adolescents with CD can avoid HLA testing, endoscopy, and anesthesia
5 PREVALENCE OF CD IN RELATION TO CHILD MORTALITY. RESULTS FROM 26 STUDIES FROM 17 COUNTRIES J Ped Gastroenterol Nutr 2017
6 DEFINITION OF COELIAC DISEASE (CD) CD is a chronic inflammatory disease characterised by flattened villi on the small bowel mucosa and is induced in genetically susceptible people by the ingestion of proline-rich and glutamine-rich proteins contained in wheat, rye and barley (gluten) Lancet 2009
7 NON COELIAC GLUTEN SENSITIVITY (NCGS) symptoms -ranging from abdominal pain to foggy mindthat improve or disappear after gluten withdrawal lack of intestinal lesion negativity of anti-transglutaminase and anti-endomysial antibodies unrelated to a specific HLA status very high prevalence (6 times >> CD!)
8 PTS DISTRIBUTION ACCORDING TO THEIR WEEKLY GLUTEN AND PLACEBO OVERALL SCORES Clin Gastroenterol Hepatol 2015
9 NCGS PROVISIONAL CONCLUSIONS although overall symptoms were worsened significantly by gluten, most patients showed approximately equal degrees of symptoms with either gluten or placebo the identification of 3 ʺtrueʺ NCGS patients does not represent crucial evidence in favor of the existence of this new syndrome we cannot exclude the possibility that these patients merely had an increased visceral or extra-intestinal sensitivity Clin Gastroenterol Hepatol 2015
10 FRUCTAN -RATHER THAN GLUTEN- CAUSES NCGS only gastrointestinal symptoms (GSRS-IBS) assessed Skodje et al, Gastroenterology 2018 a possible synergistic action of gluten + fructan (real-life scenario) not assessed
11 IS COELIAC DISEASE MIS/OVERDIAGNOSED? RESULTS OF 605 CONSECUTIVE CASES REFERRED TO UNIVERSITY OF PAVIA (1999/2005) False Predictors questioned refused Clinical diagnosis Unconventional tests Poor sample quality Marsh 1/2 lesions ttg false-positivity Can J Gastroenterol 2009
12 THE "BIASABLE" SEROLOGY IN CD most of the studies performed in centres with a specific interest in CD most of the results obtained from stored serum samples comparisons between new and old ABs untenable lack of real prospective studies (even in risk groups [expected prevalence ~ 5-10%] 500/1000 new upper GI endoscopies needed to collect 50 new true positives!) in the real world the screening power of coeliac ABs is at best questionable!
13 IS ADULT CD STILL WORTH A BIOPSY? duodenal biopsy if properly collected, processed, and evaluated does not represent a further source of misdiagnosis CD may be associated with other upper GI conditions individuals with unsuspected CD have been diagnosed in the course of endoscopic examination commercially available TTA-ELISA kits may entail a very variable performance patients not diagnosed on histological grounds, may be less compliant to GFD without a comparison of different specimens, taken at different times, diagnosis of refractory CD could be jeopardised or delayed positive serology alone would miss potential CD, the treatment and follow-up of which may differ novel multicentre, prospective, controlled studies are needed, involving also individuals assessed in primary and secondary care Lancet Gastroenterol Hepatol 2017
14 NATURAL HISTORY OF POTENTIAL COELIAC DISEASE IN ADULTS Scand J Gastroenterol 2013 some pts maintained a normal mucosa and symptoms improved after many years of GCD potential CD is not a prodrome of CD, but a separate entity that can subsequently evolve
15 EFFECT OF GFD (34 mo) ON SYMPTOMS & LESIONS IN PTS WITH POTENTIAL CD Mandile et al, JPGN 2018 caution is necessary in potential CD before attributing all the abnormalities to gluten
16 IS COELIAC DISEASE MIS/OVERDIAGNOSED? RESULTS OF 605 CONSECUTIVE CASES REFERRED TO UNIVERSITY OF PAVIA (1999/2005) False Predictors questioned refused Clinical diagnosis Unconventional tests Poor sample quality Marsh 1/2 lesions ttg false-positivity Can J Gastroenterol 2009
17 SOURCE OF MISINTERPRETATION IN ASSESSING SMALL INTESTINAL BIOPSY TANGENTIAL ARTIFACT BRUNNER ARTIFACT
18 SMALL INTESTINAL BIOPSY. PROPER HANDLING AND PROCESSING Orientation Sectioning
19 Corazza classification Oberhuber classification Marsh classification AN APPROACH TO DUODENAL BIOPSIES IN CD Infiltrative Hyperplastic Atrophic Hypoplastic 1 2 3a 3b 3c 4 A B1 B2 Serra & Jani, J Clin Pathol 2006
20 PATHOLOGIST AGREEMENT WITHIN M-H CLASSIFICATION Categories K Values M H type 0 M H type 1 M H type 2 M H type 3a M H type 3b M H type 3c Corazza et al, Clin Gastroenterol Hepatol 2007 Arguelles-Grande et al, J Clin Pathol 2012
21 REVISING PATHOLOGICAL CRITERIA FOR DIAGNOSIS OF CD (M-H or C-V?) M-H total k values C-V total k values Patey et al, J Ped Gastroenterol Nutr 2016 Bilkhoo et al, J Ped Gastroenterol Nutr 2016 Marsh et al, Gastroenterol Hepatol 2015
22 THE PATHOLOGICAL SPECTRUM OF CD M-H type 1 M-H type 3c C-V type A C-V type B2
23 DUODENAL LYMPHOCYTOSIS. KEY POINTS TO CONSIDER other possible causes autoimmune conditions viral enteritis & bacterial overgrowth Hp infection GVHd giardiasis food hypersensitivity a common response to a number of noxious and inflammatory signals Smyrk, Surg Pathol 2017
24 SERONEGATIVE (IgA & IgG) COELIAC DISEASE diagnosis relies on the histological response to a GFD after other forms of villous atrophy have been excluded family history and DQ2/DQ8 positivity are supportive criteria possible causes include concomitant immunedeficiency, GFD prior to testing, immunosuppressants, > mucosal avidity due to complications uncommon condition (2% of CD population, ~30% of seronegative villous atrophy) poor prognosis Eur J Gastroenterol Hepatol 2017 Curr Opin Gastroenterol 2018
25 ʺFALSEʺ REFRACTORY CD concurrent conditions IBS Microscopic Colitis Bacterial Overgrowth Lactase Deficiency Pancreatic Insufficiency dietary non-compliance or inadvertent gluten intake slow histological recovery after diet misinterpretation of the original biopsy - poor sample quality - non-coeliac flat mucosa Autoimmune Enteropathy CVID Olmesartan Enteropathy HIV Enteropathy GVHD
26 PITFALLS IN DIAGNOSING RCD Six patients referred with a diagnosis of refractory CD Tangential artifact Proper orientation Subtotal villous atrophy Normal mucosa Failure to respond to a GFD should always raise doubt regarding the initial diagnosis Shidrawi et al, J Clin Pathol 1994
27 CAUSES OF FLAT MUCOSA OTHER THAN COELIAC DISEASE Autoimmune enteropathy Bacterial overgrowth Primary immunodeficiency Eosinophilic gastroenteritis Collagenous sprue Cow's milk enteropathy Crohn's disease Soy protein enteropathy Tropical sprue Graft-versus-host disease Giardiasis Chemotherapy Whipple's disease Radiation damage HIV enteropathy Protein energy malnutrition Lancet 2009
28 AUTOIMMUNE ENTEROPATHY IN ADULTS Case 1 Case 2 Mayo Clinic Series May June pts (47% Fe, age 55 yr) 15/15 severe malabsorbers 13/14 E/GoAb + 80% associated AI 60% clinical improvement after immunosuppressants Lancet 1997 Clin Gastroenterol Hepatol 2007
29 HISTOLOGIC FEATURES OF ADULT AUTOIMMUNE ENTEROPATHY COMPARED WITH RCD Smyrk, Surg Pathol 2017 Sharma et al, Clin Gastroenterol Hepatol 2018
30 FLAT DUODENAL MUCOSA IN PATIENTS WITH CVID Pts. Sex Age (yrs) Histological response to a GFD Positive coeliac antibodies HLA 1 M 47 Yes EMA IgG DQ2 + 2 F 27 Yes EMA IgA-IgG DQ2 + 3 M 42 Yes EMA IgG DQ8 + 4 M 28 No EMA IgG DQ2/8-5 M 46 No None DQ2/8-6 M 35 No None DQ2/8-7 M 53 No None DQ2 + 8 M 46 No EMA IgG DQ2 + 9 M 44 No EMA IgG DQ F 59 No None DQ F 52 No None DQ2 + Am J Clin Pathol 2012
31 DUODENAL MUCOSA IN PATIENTS WITH CVID PC DEPLETION PMN INFILTRATE GVHD-like LESIONS 10/11 5/10 3/5 only in pts in whom CD not confirmed (#4-11) Am J Clin Pathol 2012
32 A 56 yr-old PHISYCIAN WITH BLOOD HYPERTENSION & TYPE 2 DIABETES 2011 diarrhoea (10mov/d) weight loss (10kg/3mo) ve - coeliac ABs BX complete villous atrophy 2012 RCD I diagnosis steroides added to GFD only mild clinical improvement BX partial villous atrophy 2013 olmesartan withdrawal BX villous regrowth symptom resolution marked weight gain
33 AUGUST 2012 HISTOLOGIC FINDINGS IN 22 PTS WITH SPRUE-LIKE ENTHEROPATHY ASSOCIATED WITH OLMESARTAN
34 OLMESARTAN SPRUE-LIKE ENTEROPATHY. PATHOLOGIC & CLINICAL SPECTRUM Burbure et al, Human Pathol 2016 in a nationwide cohort study, olmesartan exposure is associated with an increased risk of hospitalisation for intestinal malabsorption and CD relative risk increases with treatment duration no such risk exists for other ARBs (??) Basson et al, Gut 2015
35 ENTEROPATHY ASSOCIATED T-CELL LYMPHOMA (EATL) Blood 2012
36 EATL IN ADULT AUTOIMMUNE ENTEROPATHY 53-yr old woman with a 30-yr history of refractory villous atrophy coeliac ABs-, anti-enterocyte ABs+ initial response to steroids/ thiopurines perforated jejunal lymphoma death from cerebral metastasis TCRβ PCR 53-yr old woman with a 15-yr history of refractory villous atrophy coeliac ABs-, anti-enterocyte ABs+ prolonged response to steroids obstructing jejunal lymphoma death from cerebellar metastasis TCRγ PCR 252 bp 252 bp 148 bp 148 bp Malamut et al, Gastroenterology Hematol Oncol 2018
37 A 57 YEAR-OLD MAN DEAD FOR TYPE 2 EATL (MEITL) ASSOCIATED WITH CD Monomorphic medium-sized T-cells with irregular nuclei & scant CTP Invasion of LP crypt epithelium, no inflammatory background CD3+, CD4-, CD8+, CD30-, CD56+, MATK+ Array CGH profile of chromosome 9 showing deletion 9p13.1-9p24.1 & gain 9q33 - q34 Submitted
38 INDOLENT SMALL INTESTINAL CD4 + T-CELL LYMPHOMA IS A DISTINCT ENTITY 3 pts misdiagnosed for CD CD8 -, CD103 -, CD4 + T-cells clonal TCR-vβ chain indolent course Margolskee et al, PlosOne 2013
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