Celiac Disease

Definition

• Chronic enteritis secondary to gluten sensitivity

Alternate/Historical Names

• Celiac sprue
• Coeliac disease
• Gluten sensitive enteropathy
• Non-tropical sprue

Diagnostic Criteria

• Villous atrophy in small intestine
• May be variable and patchy
• Most symptomatic patients have total villous atrophy
• Defined as completely flattened villi
• Partial atrophy more common in pre-symptomatic or post-treatment patients or in relatives being screened
• Increased intraepithelial lymphocytes in small intestine may be seen with or without atrophy
• Cutoff varies by location
  • Duodenum >30 / 100 enterocytes
    • Alternative proposed is 6-12 / 20 enterocytes at the tips of villi
  • Jejunum >40 / 100 enterocytes
  • Occasionally seen in stomach and large intestine
• T cell phenotype
• CD2+, CD3+, CD8 70-90%
• Gamma delta T cell receptor
• CD3 stain is useful for identification and counting
• Intraepithelial lymphocytes evenly distributed from bottom to top of crypts or increased at tops
  • Normal distribution is decreasing from bottom to top
    • Villi must be well oriented to be certain that what appears to be the top is not a semi-tangentially cut section of mid-villus
• Identification of an abnormal distribution or of more than rare lymphocytes on H&E is a clue that it may be worth staining and counting cells
• Increased intraepithelial lymphocytes in the absence of villus atrophy is suggestive of latent or partially treated celiac disease but not specific, as it can be seen in:
  • Infections (Giardia, Helicobacter, Cryptosporidium, viruses)
  • Food allergy
  • Drug reactions (NSAIDS)
  • Immune system abnormalities
  • Inflammatory bowel disease
  • Lymphocytic colitis and gastritis
  • Morbid obesity (Harpaz)
• Chronic inflammatory infiltrate in lamina propria
• Lymphocytes, plasma cells and eosinophils most common
• Neutrophils may be seen in lamina propria and crypts (Moran 2012)
• More common in children than adults (56 vs 28%)
• Correlates with disease activity
• Other diagnoses such as infection must be ruled out
• Crypt hyperplasia
• Normal villus:crypt length ratio is 3-5:1
• Mitotic figures may be numerous
• Changes similar to the above may occasionally be seen in the stomach and large intestine
• Biopsy is required for diagnosis
• Distal duodenum is best as it avoids most other inflammatory processes
• Biopsy is required to assess the response to dietary gluten restriction
• Villous atrophy may be only partial or absent
• Intraepithelial lymphocytes and lamina propria infiltrate may be decreased or absent
• Complete return to normal may take years
• Histology of refractory disease is not as well described
• Defined as loss of clinical response to gluten free diet
• Mucosal atrophy and thinning
• Increased subepithelial collagen layer (collagenous sprue)
• Decreased CD8 expression by T cells
• Development of ulcerative jejunoileitis
• Development of enteropathy type T cell lymphoma can cause refractory disease
• The Modified Marsh Classification of histologic findings has been used to grade celiac disease
  • Simplified systems (Corazza, Roberts, Ensari) may be more reproducible
    • Grade A/Type 1: increased intraepithelial lymphocytes but no villous atrophy
    • Grade B1/Type 2: villi still present but shortened
    • Grade B2/Type 3: complete villous atrophy

Robert V Rouse MD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting, last update: 11/11/09, 12/3/14

Modified Marsh Classification of histologic findings in celiac disease (Oberhuber)

• IEL/100 enterocytes, intraepithelial lymphocytes per 100 enterocytes
• Type 0: Normal; celiac disease highly unlikely.
• Type 1: Seen in patients on gluten free diet (suggesting minimal amounts of gluten or gliadin are being ingested); patients with dermatitis herpetiformis; family members of celiac disease patients, not specific, may be seen in infections.
• Type 2: Very rare, seen occasionally in dermatitis herpetiformis.
• Type 3: Spectrum of changes seen in symptomatic celiac disease.

Simplified systems may be more reproducible (Corazza, Roberts, Ensari)

• Grade A/Type 1: increased intraepithelial lymphocytes but no villous atrophy
  • Seen in patients on gluten free diet (suggesting minimal amounts of gluten or gliadin are being ingested); patients with dermatitis herpetiformis; family members of celiac disease patients, not specific, may be seen in infections
• Grade B1/Type 2: villi still present but shortened
  • Spectrum of changes seen in symptomatic celiac disease
• Grade B2/Type 3: complete villous atrophy
  • Spectrum of changes seen in symptomatic celiac disease

Supplemental studies

Immunohistology

• CD3 or other pan-T cell marker is useful for identifying and counting T cells

Serology

• Quite sensitive and specific
• Especially useful for screening
• As 3% of celiac disease patients are IgA deficient, biopsy is necessary to rule out disease

Differential Diagnosis

• Increased intraepithelial lymphocytes are not specific
• Tropical sprue
• Prolonged post-enteritis syndrome
• Autoimmune enteropathy
• Common variable immunodeficiency
• Food allergy
• Crohn disease

Increased intraepithelial lymphocytes in the absence of villus atrophy can also be seen in the following, which must be ruled out clinically

• Infections (Giardia, Helicobacter, Cryptosporidium, viruses)
• Food allergy
• Drug reactions (NSAIDS, chemotherapy)
• Immune system abnormalities (GVHD, autoimmune enteropathy, other autoimmune diseases)

• Confined to tropics
• Responds to anti-microbial therapy
• Lacks anti-endomysial antibodies

• History of preceding viral or bacterial gastroenteritis
• Usually infantile

 

Celiac Disease	Autoimmune Enteropathy
Usually occurs in childhood or older	Usually begins under 6 months of age, but can occur in adults
Responds to gluten withdrawal	Refractory to gluten withdrawal
Anti-endomysial and - tissue transglutaminase antibodies	Anti-enterocyte antibodies
CD4 negative T cells predominate	CD4+ T cells predominate
Gamma delta T cell receptors predominate	Alpha beta T cell receptors predominate

For pediatric autoimmune enteropathy with associated polyendocrinopathy see IPEX syndrome.
Some adult autoimmune enteropathy cases have been discovered in the workup of patients thought to have celiac disease but who do not respond to removal of gluten from the diet

 

Celiac Disease	Common Variable Immunodeficiency – GI Involvement
Numerous plasma cells	Plasma cells frequently markedly decreased
Abnormal enterocyte maturation	Normal enterocyte maturation with brush border and goblet cells near lumen
Prominent villous atrophy	Villous atrophy may be mild to severe
Crypts hyperplastic	No crypt hyperplasia
Apoptosis not prominent	Apoptosis may be prominent in crypts
Anti-endomysial and - tissue transglutaminase antibodies	All antibodies generally depressed; humoral testing is not reliable in CVID

 

Food Enteropathy	Celiac Disease
May be predominantly eosinophilic infiltrate	Mixed lymphoplasmacytic and eosinophilic infiltrate
Usually presents very near birth	Usually presents in childhood to 30’s
Intraepithelial lymphocytes may be present but usually <40/HPF	Intraepithelial lymphocytes >40/HPF
Resolved by elimination of offending food from diet	Resolved by elimination of gluten from diet

 

Crohn Disease	Celiac Disease
Skip lesions predominate	Usually diffuse
Usually involves large intestine	Principal involvement is small intestine
Transmural inflammation	Mucosal inflammation
Granulomas may be seen	Granulomas absent
Anti-Saccharomyces antibody may be present	Anti-endomysial and - tissue transglutaminase antibodies

Clinical

• HLA linked, first degree relatives at 10x risk
• Serologic screening of relatives is frequently used to find subclinical, pre-symptomatic cases
• May present at any age but most in childhood to thirties
• Presentation in childhood
• Diarrhea, steatorrhea
• Growth retardation, weight loss
• Abdominal pain
• Late onset presentation (>45)
• Short stature
• Infertility, amenorrhea
• Iron or folate deficiency
• Osteoporosis
• Diarrhea not prominent
• Malabsorption only on tests
• Refractory sprue
• Defined as loss of clinical response to gluten free diet
• Causes include
• Failure to follow diet, intentionally or unintentionally
• Development of collagenous sprue
• Development of ulcerative jejunoileitis and enteropathy type T cell lymphoma
• Wrong initial diagnosis
• Development of other disease
• Associated diseases
• Dermatitis herpetiformis (DH)
• 70-90% of DH patients have celiac disease
• 10% of celiac disease patients have DH
• Lymphocytic colitis, collagenous colitis, collagenous gastritis
• Hyposplenism
• Various autoimmune diseases
• Insulin dependent diabetes mellitus
• Sjogren syndrome
• Autoimmune liver disease
• Autoimmune thyroiditis
• Autoimmune myocarditis
• Systemic lupus erythematosus
• Increased risk of esophageal squamous carcinoma
• Increased risk of small intestinal carcinoma
• Increased risk of enteropathy type T cell lymphoma
• Some of these can occur even in patients with sub-clinical celiac disease
• Gluten free diet can resolve or decrease the risk of occurrence of these disorders

Bibliography

• Noffsinger A, Fenoglio-Preiser CM, Maru D, Gilinisky N.  Gastrointestinal Diseases, AFIP Atlas of Nontumor Pathology, First Series, Fascicle 5, 2007.
• Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol. 1999 Oct;11(10):1185-94.
• Corazza GR, Villanacci V, Zambelli C, Milione M, Luinetti O, Vindigni C, Chioda C, Albarello L, Bartolini D, Donato F. Comparison of the interobserver reproducibility with different histologic criteria used in celiac disease. Clin Gastroenterol Hepatol. 2007 Jul;5(7):838-43.
• Di Sabatino A, Corazza GR. Coeliac disease. Lancet. 2009 Apr 25;373(9673):1480-93.
• Ensari A. Gluten-sensitive enteropathy (celiac disease): controversies in diagnosis and classification. Arch Pathol Lab Med. 2010 Jun;134(6):826-36.
  
• Robert ME. Gluten sensitive enteropathy and other causes of small intestinal lymphocytosis. Semin Diagn Pathol. 2005 Nov;22(4):284-94.
  
• Brown I, Mino-Kenudson M, Deshpande V, Lauwers GY. Intraepithelial lymphocytosis in architecturally preserved proximal small intestinal mucosa: an increasing diagnostic problem with a wide differential diagnosis. Arch Pathol Lab Med. 2006 Jul;130(7):1020-5.
• Walker MM, Murray JA. An update in the diagnosis of coeliac disease. Histopathology. 2011 Aug;59(2):166-79.
• Moran CJ, Kolman OK, Russell GJ, Brown IS, Mino-Kenudson M. Neutrophilic infiltration in gluten-sensitive enteropathy is neither uncommon nor insignificant: assessment of duodenal biopsies from 267 pediatric and adult patients. Am J Surg Pathol. 2012 Sep;36(9):1339-45