Approach to Duodenal Mucosal Biopsies Jeffrey Goldsmith, MD Beth Israel Deaconess Medical Center Children’s Hospital Boston Harvard Medical School Boston, Massachusetts Outline Normal Peptic Duodenitis Celiac Disease Why Biopsy? Peptic injury Other inflammatory disorders Malabsorptive conditions Infections Neoplasms Normal Duodenal Mucosa: Things to Remember Altered villous architecture over: – Lymphoid nodules – Prominent Brunner glands Lymphoid nodules: Increased in children Mononuclear inflammation Eosinophils Normal Duodenal Mucosa: Things to Remember Artifacts: – Poor orientation – Squished Brunner’s Glands + = Brunner’s Brunner’s Paste Paste Peptic Duodenitis Peptic Duodenitis Overexposure to or excessive acid Typically confined to proximal half of duodenum Variable endoscopic appearance: – Erythema/friability – Nodularity – Erosion/ulcer Peptic Duodenitis Histopathology Active phase Chronicity – Increased mononuclear infiltrate – Variably decreased villous height – Variable crypt hyperplasia – Foveolar/gastric metaplasia of epithelium – Intramucosal Brunner gland hyperplasia – H. pylori colonization in metaplastic epithelium Peptic Duodenitis Differential Diagnosis Drug-induced NSAIDs) Crohn’s injury (typically disease Zollinger-Ellison syndrome Take Home Point – Minimal criteria for the diagnosis of peptic duodenitis: Intraepithelial neutrophils Foveolar/gastric metaplasia Duodenum, biopsy: – Chronic active duodenitis. Celiac Disease Definition Celiac disease (CD) is an inflammatory disease in which certain predisposed individuals develop a destructive inflammatory response to certain proline-rich, alcohol soluble proteins in grains. Significance – Sequelae: Morbidity Neoplasia – Enteropathy-associated T-cell lymphoma – Carcinoma Refractory sprue Significance Diagnosis and adherence to glutenfree diet can lead to resolution of symptoms and decreased risk of neoplastic complications. Epidemiology Thought to be uncommon when CD was first described. Now prevalence approximately 1:100-300 in western countries. – Less common in Latino community – Rare in Asian populations – Middle-east and India: similar prevalence as west. Pathogenesis APC Clinical Diagnosis Classic symptoms – Steatorrhea, abdominal distension, lethargy in adults – Abdominal distension, diarrhea, weight loss, irritability in children Symptomatology can be subtle and diverse – 4-6% of patients with iron deficiency anemia have celiac disease Clinical Diagnosis http://www.aafp.org/afp/980301ap/pruessn.html Clinical Diagnosis Dermatitis Herpetiformis – Associated with symptomatic CD in 3050% of patients. – Also strongly associated with the subsequent development of CD in asymptomatic patients. – Tx: Gluten free diet Dapsone Clinical Diagnosis Other clinical associations – IgA deficiency – Diabetes mellitus – Sjogren’s syndrome – Autoimmune thyroiditis – Autoimmune liver disease – Down’s syndrome – Lymphocytic colitis / lymphocytic gastritis Clinical Diagnosis Serology – IgA anti-tissue transglutaminase (TTG) & IgA anti-endomysial antibodies: Thought to be specific and sensitive (~ 95%) – IgA deficient patients – Deamidated gliadin IgG/A (DGP): Used mostly in IgA deficient patients. Genetic testing -- HLA DQ2 / DQ8 Clinical Diagnosis Endoscopic appearances – Scalloped folds – Increased vascularity – Atrophy – Normal Pathologic Diagnosis Pathologic Diagnosis Pathologic Diagnosis Marsh Classification (Modified by Oberhuber) Marsh Type IELs per 100 enterocytes Crypt Hyperplasia Villous Architecture 0 <40 Absent Normal 1 >40 Absent Normal 2 >40 Present Normal 3a >40 Present Mild Atrophy 3b >40 Present Marked Atrophy 3c >40 Present Complete Atrophy Pathologic Diagnosis – Villous atrophy / Crypt hyperplasia Crypt hyperplasia occurs first Villous atrophy variable Not specific – Tangential sectioning – Late change of CD Pathologic Diagnosis Marsh 0 Marsh 3A Marsh 3C Pathologic Diagnosis – Intraepithelial lymphocytosis CD8 positive Tlymphocytes – Most specific and sensitive histologic feature – Normal number of IELs classically less than 40/100 enterocytes Pathologic Diagnosis Pathologic Diagnosis – Variability of intraepithelial lymphocytosis along length of villus – IELs over mucosal lymphoid aggregates not significant Pathologic Diagnosis – Increased IELs may be only finding. ‘Latent’ celiac disease - 5-10% of patients have CD Patients with dermatitis herpetiformis 1st degree relatives of CD patients Known CD patients on gluten-free diet who are ingesting small amounts of grain Pathologic Diagnosis Pathologic Diagnosis Pathologic Diagnosis Histologic Variability From fragment to fragment – 50% of cases Within biopsy fragments – 36% of cases Site to site – 10% showed changes in bulb only. Weir DC, Glickman JN, Roiff T, Valim C, Leichtner AM: Variability of histopathological changes in childhood celiac disease, Am J Gastroenterol 2010 105:207-212 Pathologic Diagnosis Number of duodenal biopsies Percent positive yield 1 ~ 70% 2 ~ 80% 3 85 – 90% >4 > 95% Adults vs Children Marked villous atrophy seen in 86% of children vs 52% of adults – Degree of villous atrophy was inversely correlated with patient age Vivas S, Ruiz de Morales JM, Fernandez M, Hernando M, Herrero B, Casqueiro J, Gutierrez S: Age-related clinical, serological, and histopathological features of celiac disease, Am J Gastroenterol 2008, 103:2360-2365 Refractory Celiac Disease Symptoms despite adherence to a gluten free diet – Unrecognized intake of gluten – Development of autonomous lymphoproliferation Refractory Celiac Disease Responsive Celiac Disease: CD3+ IELs ~ CD8+ IELs If CD8+ cells decrease to less than 50% of CD3+ cells: – Poor response to steroids – Increased risk of progression to T-cell lymphoma CD3 CD8 Mimics of CD – Even in combination, villous architecture changes and increased IELs are not specific for CD – The changes must be interpreted in context of the clinical setting Mimics of CD 1. 2. 3. 4. 5. 6. 7. Peptic duodenitis Infections Allergic enteritis Crohn’s Disease Tropical Sprue Autoimmune Enteropathy Immunodeficiencies Mimics of CD Mimics of CD Mimics of CD – 1. Peptic duodenitis: Usually increased IELs are not in the spectrum of peptic duodenitis** ** recent reports of increased duodenal IELs in patients with H. pylori gastritis Mimics of CD Mimics of CD Mimics of CD – 1. Peptic duodenitis: One must be especially careful when interpreting duodenal biopsies taken from the bulb: – Changes of peptic duodenitis (i.e. villous architecture changes) most severe here. If there are increased IELs, mention celiac disease as a possibility Mimics of CD – 2. Infections: Giardia – find organisms on biopsy Viral enteritis (usually in children) – can be difficult to distinguish from CD – Clinical correlation important Bacterial overgrowth Mimics of CD Mimics of CD Mimics of CD – 3. Food allergies Typically cow’s milk and eggs – Often increased numbers of lamina propria eosinophils are present – Response to elimination diet Mimics of CD – 4. Upper GI tract Crohn’s Disease Usually shows focal and destructive acute inflammation with crypt abscess formation Granulomas Mimics of CD Mimics of CD Mimics of CD – 5. Tropical Sprue Can be histologically identical to CD Responds to antibiotics and folate Mimics of CD – 6. Autoimmune enteropathy Rare disorder more common in infants Associated with anti-enterocyte / anti-goblet cell antibodies Usually destructive Mimics of CD Mimics of CD Mimics of CD Mimics of CD – 7. Immunodeficiency States Most commonly common variable immunodeficiency (CVID) – Absent or markedly decreased plasma cells. – Marked lymphoid hyperplasia – Increased apoptotic enterocytes Mimics of CD Mimics of CD Take Home Points – 1. Especially when changes are mild, findings are not specific for celiac disease. – 2. Be Careful In the Bulb! When there are increased IELs, celiac disease is a distinct possibility. Take Home Points – Find the Mimics! – 1. Giardiasis: Organisms. – 2. Bacterial Overgrowth: Significant lymphoid hyperplasia with germinal centers. – 3. Crohn’s Disease: Focal enhanced pattern of acute inflammation in duodenal / gastric biopsies. – 4. Allergy: Eosinophils in the lamina propria. – 5. Autoimmune Enteropathy: Lack of goblet / Paneth cells with destructive inflammation. – 6. Common Variable Immunodeficiency: Lack of plasma cells. Take Home Points – Duodenum, biopsy: Duodenal mucosa with complete villous atrophy, crypt hyperplasia, and marked intraepithelial lymphocytosis; see note. Note: The changes are consistent with celiac disease in the appropriate clinical setting.
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