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Small bowel (small intestine)

Malabsorption

Celiac sprue


Reviewer: Hanni Gulwani, M.D. (see Reviewers page)
Revised: 14 December 2012, last major update August 2012
Copyright: (c) 2003-2012, PathologyOutlines.com, Inc.

General
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● Major cause of malabsorption - almost all adults in North America with severe villous abnormality and crypt hyperplasia have celiac sprue
● Also called nontropical sprue, gluten-sensitive enteropathy, celiac disease

Pathophysiology
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● Individuals with genetic predisposition have increased immunological responsiveness to prolamins such as dietary wheat gliadin and similar proteins in barley, rye, possibly oats
● Gluten is an alcohol soluble, water insoluble protein component in wheat, oat, barley, rye
● Gluten is mostly made up of 2 groups of proteins: ethanol-soluble gliadins and ethanol-insoluble glutenins
● Gliadin contains chiefly proline and glutamine amino acids
● αGliadin is most toxic to celiac patients
● Gliadin serves as a substrate for transglutaminase (85-kDa enzyme) and becomes cross-linked to it creating a neoantigen Ė induces immune response
● Disease is due to abnormal cell mediated immunity - gluten exposure causes accumulation of intraepithelial cytotoxic T cells and helper T cells in lamina propria

Clinical features
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● Affects 1 per 200-300 whites in Western countries, onset typically in childhood, rare in Africa, Japan, China
● HLA DQ alpha/beta heterodimer appears to confer susceptibility (90% have DQw2 HLA on #6), linked to HLA B8 (80%)
● Also associated with lymphocytic gastritis / colitis, selective IgA deficiency, type 1 diabetes, Sjogrenís syndrome, autoimmune thyroiditis
● Does not appear to be associated with H. pylori gastritis (Am J Gastroenterol 2006;101:1880)

Symptoms:
● Newborns: diarrhea and failure to thrive
● Symptoms of episodic diarrhea, flatulence, weight loss, fatigue begin as late as age 40; also abdominal pain and distention, weight loss (Clin Med Res 2004;2:71)
● Clinical and microscopic improvement after dietary changes

Late onset:
● 40ís and 50ís
● Symptoms of short stature, infertility, peripheral neuropathy, iron or folate deficiency, osteoporosis, indigestion, dental enamel defects

Complications:
● Long term risk of malignant disease is 2x normal, usually T cell intestinal lymphomas
● Also GI or breast carcinomas or esophageal squamous cell carcinoma

Seronegative celiac disease
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● Individuals lack serum autoantibodies, have normal villous architecture or mild atrophy
● Increased intraepithelial lymphocytes (IEL)
● Tissue transgultaminase IgA immune deposits are detectable in lamina propria

Classification
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Old Marsh-Oberhuber classification (5 states of small-intestinal mucosal injury (types 0Ė4)):
● Type 0: Preinfiltrative: normal small-intestinal mucosa with less than 30 IELs per 100 enterocytes
● Type 1: Infiltrative type: normal villous and crypt architecture ( >3 1) and an increased IELs (>30 IELs per 100 enterocytes)
● Type 2: Infiltrative-hyperplastic type: normal villous architecture and crypt hyperplasia with an increased number of IELs-rare
● Type 3: Destructive (flat mucosa) type of CD lesion: 3 different subgroups depending on the degree of villous atrophy
  ● Type 3a: Mild villous atrophy with villous to crypt ratio of <3 1 or 2 1, and increased IELs
  ● Type 3b: Marked villous atrophy with villous to crypt ratio of <1 1, and increased IELs
  ● Type 3c: Total villous atrophy with completely flat mucosa and increased IELs
● Type 4: Atrophic type (hypoplastic); very rare pattern, flat mucosa with only a few crypts and near-normal IEL counts

New classification (Corazza and Villanacci):
● Grade A: Nonatrophic, with normal crypt and villous architecture and increased IELs (>25 IELs per 100 enterocytes)
● Grade B1: Atrophic, with villous to crypt ratio <3 1, but villi are still detectable and IELs are increased (>25 IELs per 100 enterocytes)
● Grade B2: Atrophic and flat, villi are not detectable and increased IELs are noted (>25 IELs per 100 enterocytes)


Comparison of classification systems

Diagnosis
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● Antitransglutaminase, antigliadin or antiendomysial antibodies plus clinical malabsorption plus typical histologic findings plus improvement in symptoms and histology after gluten withdrawal

Laboratory
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● Elevated serum IgA except in those with IgA deficiency (more common in these patients than normals)
● Also IgA anti-transglutaminase, antiendomysial, antireticulin and antigliadin antibodies


Sensitivity of various antibodies

Serum IgA:
● Used to monitor compliance with gluten-free diet

Antitransglutaminase antibody:
● Sensitive marker of disease

IgA anti-endomysial antibody:
● Detect with monkey esophageal tissue
● Sensitive and specific, although also positive in dermatitis herpetiformis

IgA and IgG anti-gliadin antibody:
● Less sensitive than antitransglutaminase and antiendomysial antibodies

Anti-reticulin antibody:
● In 40%, but nonspecific
● Also seen in Crohn's disease, myasthenia gravis, Sjogrenís, other

Case reports
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● 56 year old woman with long history of untreated celiac sprue (Case of the Week #127)

Treatment
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● Improves clinically and microscopically after dietary withdrawal of wheat gliadins and related grain proteins

Gross description
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● Usually flat, scalloped mucosa
● May be normal

Micro description
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Note: diagnosis requires clinical correlation - pathology report can only state "consistent with celiac sprue"
● Increase in intraepithelial lymphocytes, most sensitive marker is 40+ lymphocytes per 100 surface or upper crypt enterocytes
● Early-clustering of 12+ lymphocytes at tip of villi and extending evenly down the sides of the villus (Mod Pathol 2003;16:342)
● Diffuse enteritis with marked atrophy or total loss of villi
● Fat globules in surface epithelium, enterocytes have stratified nuclei, lose their brush border, increased crypt mitotic figures
● Crypts are elongated and hyperplastic, but overall mucosal thickness is the same
● Also increase in plasma cells in lamina propria
● Changes more marked in proximal small bowel (greater exposure) and abnormalities recede last here after gluten withdrawal
● Significant duodenal neutrophilia often noted in children, associated with more active disease
● Disease activity is proportional to eosinophilic infiltration and foveolar metaplasia (Am J Surg Pathol 2012;36:1339)
● Do not overdiagnose on biopsy based on minimal and nonspecific histologic changes, as diagnosis has lifelong implications (Arch Pathol Lab Med 2008;132:1594)

Micro images
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Marsh-Oberhuber classification


Marsh Type I & III lesions


Various images


Case of the Week #127

Virtual slides
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Small intestine

Differential diagnosis
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● Autoimmune enteropathy: crypt injury or destruction, anti-enterocyte antibodies, typically in first 6 months of life
● Common variable immunodeficiency: no plasma cells, marked lymphoid hyperplasia, often Giardia infection
Crohnís disease
Dermatitis herpetiformis: associated with gluten-sensitive enteropathy but also has skin lesions
● Duodenal intraepithelial lymphocytosis with normal villous architecture: associated with H. pylori infection, but no other features of celiac disease (Mod Pathol 2005;18:1134)
● Infectious enteritis: prominent neutrophils, normal intraepithelial lymphocytes
● Kwashiorkor
● Morbid obesity: intraepithelial lymphocytosis in architecturally normal small intestinal mucosa (Arch Pathol Lab Med 2007;131:344)
● Other protein allergies: sprue symptoms disappear and reappear if offending substance is withdrawn / reintroduced
Tropical sprue, severe: no antiendomysial antibodies, responds to antibiotics and folate

Differential diagnosis of intraepitheliial lymphocytes
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H.Pylori associated gastroenteritis, nongluten food hypersensitivity, infections (giardia, cryptosproridia), bacterial overgrowth, drugs (NSAIDís), IgA deficiency, common variable immunodeficiency, Crohnís disease, small bowel allograft rejection (Arch Pathol Lab Med 2010;134:826)


Table

Additional references
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J Clin Pathol 2005;58:573, Arch Pathol Lab Med 2012;136:735

End of Small bowel (small intestine) > Malabsorption > Celiac sprue


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