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Small bowel (small intestine)


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.


● 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


● 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

● 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)

● 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

● 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

● 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


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


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


● 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

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


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

Gross description

● Usually flat, scalloped mucosa
● May be normal

Micro description

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

Marsh-Oberhuber classification

Marsh Type I & III lesions

Various images

Case of the Week #127

Virtual slides

Small intestine

Differential diagnosis

● 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

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)


Additional references

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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