Inflammatory bowel disease

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Inflammatory bowel disease, abbreviated IBD, is the bread 'n butter of gastroenterology, and a significant number of gastrointestinal pathology specimens.

It exists in two main flavours:

  • Crohn's disease (CD).
  • Ulcerative colitis (UC).

Both are associated with an increased risk of colorectal carcinoma.[1]

Clinical

  • It is important to differentiate UC and CD as the management is different.
  • UC patients get pouches... CD patients do not.
    • It is said that: There 's nothing like a pouch to bring out Crohn's disease.[2]
  • People with long standing IBD have an increased risk for:

Extra-intestinal manifestations of inflammatory bowel disease

Mnemonic (family-rated version) excellent cardiac surgery is pleasant and appreciated:

Molecular

  • NOD2[5] (AKA CARD15) variants are associated with stricturing CD, early need for surgery and recurrence.[6]

General clinical differential diagnosis

  • Crohn's disease.
  • Ulcerative colitis.
  • Infective colitis/enteritis.
  • Ischemic colitis/enteritis.
  • Radiation colitis.

Others:

Specimens

  • Biopsies for diagnosis.
  • Surveillance biopsies - to rule-out dysplasia.
  • Resections for disease that has failed medical management.
  • Resections for dysplasia associated with inflammatory bowel disease.

Notes:

  • Biopsies for diagnosis should specify the (anatomical) site:
    • Slight gradients exist in the large bowel that can be exploited for diagnostic purposes if the site information is known, for example:
      • Paneth cell distal to the splenic flexure are abnormal.
      • Ulcerative colitis is often more severe distally - even in a pancolitis, as the disease starts in the rectum and progresses toward the cecum.
  • Surveillance biopsies should specify the (anatomical) site - so, it possible to find any site of interest on a follow-up colonoscopy.[7]

Spanking the clinician for submitting it all in one bottle

COLON (SITE NOT FURTHER SPECIFIED), BIOPSIES:
- MODERATE CHRONIC ACTIVE COLITIS.
- NEGATIVE FOR DYSPLASIA.
- PLEASE SEE COMMENT.

COMMENT:
The sections show colorectal-type mucosa with focal cryptitis and rare neutrophilic crypt
abscesses.  

Mild architectural changes, suggestive of a chronic colitis, are present. No granulomas are
identified. Lymphoid aggregates with germinal centre formation are present in multiple
fragments.  The lamina propria has abundant plasma cells throughout the fragments; no 
fragments have apparent relative sparing. 

Paneth cells are present focally; however, the significance of the paneth cells cannot 
determined as the biopsy sites are not known. 

The findings are compatible with inflammatory bowel disease and chronic active infectious
colitides. Clinical correlation is suggested.

Microscopic

Features helpful for the diagnosis of IBD - as based on a study:[8]

  1. Basal inflammation, i.e. crypt base, plasmacytosis with severe chronic inflammation.
    • Basal cell plasmacytosis makes an infectious etiology less likely.[9]
    • "Basal plasmacytosis" = plasma cells in the lamina propria between the crypts and muscularis mucosae.[10]
  2. Crypt architectural abnormalities.
    • Atrophy = less glands ~ 3-4 glands/mm (normal = 7-8 glands/mm).
    • Branching = common (normal = very rare branching).
    • Distortion = bent glands, marked size variation (normal = "rack of test tubes").
  3. Distal Paneth cell metaplasia.
    • Paneth cells should not be in the left colon[11] - if you see 'em think of IBD and other long-standing injurious processes.
    • Some claim that (friendly right colonic) paneth cells and paneth cell metaplasia look quite different and can be distinguished.[12]
    • Paneth cells have basal nuclei and coarse luminal granules.[13]
      • They should not be confused with endocrine cells -- these have apical nuclei and fine granules.
      • They should not be confused with intraepithelial eosinophils -- have smaller (~1/2) more intensely red granules.

Notes:

  1. Microscopic features can be remembered by mnemonic CPP: Crypts (abnormal), Plasmacytosis, Paneth cells where they don't belong.
  2. If you see architectural distortion (e.g. crypt branching) in the left colon, look for Paneth cells.
  3. The hepatic flexure is considered the divider for normal paneth cells and abnormal paneth cells, i.e. paneth cells proximal to the hepatic flexure are normal; paneth cells distal to the hepatic flexure are abnormal.[14]
  4. Stretching of tissue may mimic atrophy; tip-off it is artefact: thinning of mucosa.[9]

Images:

Grading

  • Several systems exists.[9]
  • One that is often cited is by Gupta et al.[15]

Grading schemes for IBD in a table

Nil Mild Moderate Severe
"A grading scheme"[9] - cryptitis PMN abscesses erosions
Gupta[15] "0" (nil) "1" (<50% of crypts
have PMNs)
"2" (>50% of crypts
have PMNs)
"3" (presence of
ulcers or erosions)

Crohn's disease vs. ulcerative colitis

Robbins

UC features:[16]

  • Mucosal involvement -- sometimes submucosa.
  • No skip lesions.
  • Colon/rectum only.
    • UC may have 'ileal backwash' -- mild ileal inflammation due to backwash of inflammatory soup from colon.
  • "No granulomas".
    • Superficial granulomas in the mucosa are non-specific, especially if they are beside an inflammed crypt, i.e. they may be present in UC.[17][18]
      • Deep granulomas are specific for Crohn's disease.

Example of a superficial granuloma that is non-specific, i.e. this could be UC or CD:

Kirsch

Features of UC[9] - memory device DDDR:

  • Diffuse inflammation.
  • Diffuse arch. changes.
  • Diffuse atrophy.
  • Rectal involvement.

Words of caution

The following may be present in UC:[9]

  • Cecal patch (cecal involvement without pancolitis).
  • Patchy involvement
    • Esp. in Tx'ed patients.
    • Esp. in children.
  • Ileitis - esp. in the context of severe pancolitis; known as backwash ileitis.
  • Deep inflammation (in a fissure).
  • Upper GI tract involvement -- see below.

Upper gastrointestinal tract involvement

  • The old dogma was upper GI tract = Crohn's disease.

Characteristics of upper GI tract UC:[19]

  • Most common:
    1. Focal gastritis.
    2. Mixed basal inflammation and superficial plasmacytosis in the stomach.
  • Unique:
    • Diffuse chronic duodenitis.
    • ~ 10% of UC patients.
    • ~ 40% of UC + colectomy + pouchitis.

A tabular comparison

Gross pathology:

Feature Crohn's disease Ulcerative colitis
Lesion distribution patchy diffuse
Strictures maybe no
Perianal disease yes/no no
Rectal involvement no yes
Ileal involvement yes, classic usu. no; seen in pancolitis
Upper GI tract involvement yes yes (gaining acceptance)
Associated with PSC not classically yes

Sign out

Quiescent inflammatory bowel disease

Used when:

  1. Non-specific "minimal abnormalities" are present.
  2. There is a history of inflammatory bowel disease.

"Minimal abnormalities" - features:

  • Apoptosis.
  • Macrophages in the lamina propria.
  • Lymphoid nodules.
  • Abundant plasma cells in the lamina propria.
COLON, BIOPSIES:
- QUIESCENT INFLAMMATORY BOWEL DISEASE.
- NEGATIVE FOR DYSPLASIA.

Mild inflammation

SIGMOID COLON, BIOPSY:
- MILD ACTIVE COLITIS WITH CHRONIC CHANGES, SEE COMMENT.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
No granulomata are identified.  Mild architectural changes are present.

The findings are compatible with inflammatory bowel disease or an infectious
etiology. Clinical correlation is required.

Specific diagnoses

Ulcerative colitis

  • Often abbreviated as UC.

General

  • May be associated with toxic megacolon.

Epidemiology:

Gross

  • Conventionally considered to be contiguous, i.e. no "skip lesions", with rectal involvement being most severe.
  • Dependent on the study one reads... rectal sparing may be seen in 15% of UC patients.[22]

Microscopic

Features:

  • Inflammation:
    • Active:
      • Neutrophils:
        • Intraepithelial (cryptitis).†
        • Clusters in crypts (crypt abscesses).
        • Erosions.
    • Chronic:
      • Architectural distortion.
      • Basal plasmacytosis.
      • Foveolar metaplasia.
      • Paneth cell metaplasia (distal).
    • Lack of granulomas.

Notes:

  • †Neutrophils are usually numerous in the lamina propria in minimal/mild active inflammation.
  • No full wall-thickness inflammation.
  • Epithelial apoptosis correlated with inflammation.[23]

DDx:

Sign out

SIGMOID COLON, BIOPSY:
- MODERATE ACTIVE COLITIS WITH CHRONIC CHANGES, SEE COMMENT.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
No granulomata are identified. The sampled mucosa is diffusely inflamed. Crypt drop-out and
architectural distortion are present.

The findings are consistent with inflammatory bowel disease; however, an infectious etiology
should be considered as a possibility.
SIGMOID COLON, BIOPSY:
- MILD ACTIVE COLITIS, SEE COMMENT.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
No granulomata are identified.
A. RIGHT COLON, BIOPSY:
- MODERATE ACTIVE COLITIS, SEE COMMENT.
- NEGATIVE FOR DYSPLASIA.

B. LEFT COLON, BIOPSY:
- MODERATE-TO-SEVERE CHRONIC ACTIVE COLITIS, SEE COMMENT.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
No granulomata are identified. The mucosa is diffusely inflamed. Architectural distortion
is present in the left colon.  The findings are consistent with ulcerative colitis;
however, an infectious etiology should be considered as a possibility.
RECTUM, BIOPSY:
- MODERATE DIFFUSE CHRONIC ACTIVE PROCTITIS.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
No definite granulomata are identified. Crypt drop-out is present.
Within the proper clinical context, these are findings of 
inflammatory bowel disease.

Inactive disease

SIGMOID COLON, BIOPSY:
- CHRONIC COLITIS, SEE COMMENT.
- NEGATIVE FOR ACTIVE COLITIS.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
The sections show chronic changes (basal plasmacytosis, marked crypt architectural
distortion, crypt branching); however, no active colitis is present. Also, lamina propria
neutrophils, which are often easy to identify in an active colitis, are not apparent.
Appreciable numbers of lamina propria eosinophils are present and focally intraepithelial.
No granulomas are identified. Clinical correlation is required.

Surveillance

A. ASCENDING COLON, BIOPSY:
- COLONIC MUCOSA WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR ACTIVE COLITIS.
- NEGATIVE FOR DYSPLASIA.

B. TRANSVERSE COLON, BIOPSY:
- COLONIC MUCOSA WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR ACTIVE COLITIS.
- NEGATIVE FOR DYSPLASIA.

C. DESCENDING COLON, BIOPSY:
- COLONIC MUCOSA WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR ACTIVE COLITIS.
- NEGATIVE FOR DYSPLASIA.

D. SIGMOID COLON, BIOPSY:
- COLONIC MUCOSA WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR ACTIVE COLITIS.
- NEGATIVE FOR DYSPLASIA.

E. RECTUM, BIOPSY:
- RECTAL MUCOSA WITHOUT APPARENT PATHOLOGY.
- NEGATIVE FOR ACTIVE COLITIS.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
Morphologically benign lymphoid aggregates are found focally. No granulomas are
identified. Minimal architectural changes are seen focally.
A. CECUM, BIOPSY:
- QUIESCENT INFLAMMATORY BOWEL DISEASE.
- NEGATIVE FOR DYSPLASIA.

B. ASCENDING COLON, BIOPSY:
- QUIESCENT INFLAMMATORY BOWEL DISEASE.
- NEGATIVE FOR DYSPLASIA.

C. COLON, HEPATIC FLEXURE, BIOPSY,
- QUIESCENT INFLAMMATORY BOWEL DISEASE.
- NEGATIVE FOR DYSPLASIA.

D. TRANSVERSE COLON, BIOPSY:
- QUIESCENT INFLAMMATORY BOWEL DISEASE.
- NEGATIVE FOR DYSPLASIA.

E. COLON, SPLENIC FLEXURE, BIOPSY:
- QUIESCENT INFLAMMATORY BOWEL DISEASE.
- NEGATIVE FOR DYSPLASIA.

F. DESCENDING COLON, BIOPSY:
- QUIESCENT INFLAMMATORY BOWEL DISEASE.
- NEGATIVE FOR DYSPLASIA.

G. SIGMOID COLON, BIOPSY:
- QUIESCENT INFLAMMATORY BOWEL DISEASE.
- NEGATIVE FOR DYSPLASIA.

H. RECTUM, BIOPSY
- QUIESCENT INFLAMMATORY BOWEL DISEASE.
- NEGATIVE FOR DYSPLASIA.

COMMENT:
No granulomas are identified. Mild architectural distortion is present. No active
inflammation is identified. Scattered mucosal lymphoid nodules with germinal center
formation are present.

Micro

The sections show focal intraepithelial neutrophils (cryptitis). No crypt abscesses are identified. Granulation tissue is present. There is focal Paneth cell metaplasia and foveolar metaplasia. No granulomata are identified.

Crohn's disease

  • Often abbreviated as CD.

General

Associations:[24]

  • High socioeconomic status.
  • Family history of IBD.
  • City dwellers.
  • Not breastfed.

Treatment:

  • Immune suppression.
  • Surgery considered treatment of last resort.

Gross

  • Aphthous ulcer - first gross finding of IBD.
  • Transmural inflammation, i.e. full thickness of bowel wall.
  • Creeping fat (also "fat wrapping" and "fat hypertrophy"[25]) - abundant fat, fat on anti-mesenteric side of the bowel.[26]
    • Definition: fat on more than 50% of the intestinal surface.[25]
    • DDx of creeping fat: ulcerative colitis, sclerosing mesenteritis, mesenteric panniculitis, epiploic appendagitis, omental infarction, gastrointestinal complication a renal transplant, idiopathic segmental ureteritis.[27]
    • Can be seen radiologically.
  • Cobblestone appearance -- may be described as such on endoscopy; due to edema.
  • Serpiginous ulcers.

Notes:

  • Grossly, the margins should be clear of disease; the surgical clearance and microscopic involvement are not considered important.[28]
  • The term creeping fat may be used in the context of a vasculitis outside of the abdominal cavity.[27]

Microscopic

Features:[8]

  • Segmental crypt architectural abnormalities.
  • Mucin depletion -- less goblet cells. (???)[29]
  • Mucin preservation at the active sites.
  • Focal chronic inflammation without crypt atrophy.
  • Pseudopyloric mucous glands (AKA pyloric gland metaplasia).[30]
    • Round glands with abundant pale cytoplasm - stubby champagne flute.
    • Usually in the deep aspect of the mucosa.
      • Look somewhat similar to Brunner's glands.

DDx:

Images

www:

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Biopsies

TERMINAL ILEUM, BIOPSY
	- PATCHY MILD ACTIVE ILEITIS.

COMMENT:
No granulomas are identified. An infective etiology should be considered, as 
it cannot be definitely excluded on pathologic grounds.  
Classic
A. TERMINAL ILEUM, BIOPSY
	- MODERATE GRANULOMATOUS ILEITIS.

B. CECUM, BIOPSY:
	- MILD PATCHY ACTIVE CECITIS.

C. SIGMOID COLON, BIOPSY: 
	- CHRONIC INFLAMMATORY CHANGES. NO ACTIVE COLITIS. 

COMMENT:
The histomorphological findings (patchy inflammation, granulomas, ileitis, paneth cell 
metaplasia, crypt loss and crypt elongation) are suggestive of Crohn's disease. An infective 
etiology should be considered, as it cannot be definitely excluded on pathologic grounds. 
Quiescent Crohn's disease
DESCENDING COLON, BIOPSY:
- COLONIC MUCOSA WITH PROMINENT LAMINA PROPRIA PLASMA CELLS.
- NEGATIVE FOR ACTIVE COLITIS.

COMMENT:
Minimal architectural changes consistent with chronic inflammation are present. There are 
no granulomas. No dysplasia is identified. The findings are compatible with quiescent 
Crohn's disease.

Resection

TERMINAL ILEUM, CECUM, AND APPENDIX, CECUM-ILEUM RESECTION:
- CHRONIC ACTIVE GRANULOMATOUS ILEITIS -- INCLUDING:
-- MURAL MICROABSCESS FORMATION.
-- SEROSITIS.
-- A STRICTURE.
-- DEEP ULCERATION (AT LEAST THROUGH THE MUSCULARIS PROPRIA).
- PERIAPPENDICITIS, NEGATIVE FOR APPENDICITIS.
- CECUM WITHIN NORMAL LIMITS.
- TEN LYMPH NODES NEGATIVE FOR MALIGNANCY ( 0 POSITIVE / 10 ).
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

COMMENT:
The sections show patchy transmural inflammation and skip lesions.
The findings are consistent with Crohn's disease.
TERMINAL ILEUM, CECUM, APPENDIX, AND ASCENDING COLON, RIGHT HEMICOLECTOMY:
- CHRONIC ACTIVE ILEITIS -- INCLUDING:
-- INFLAMMATORY PSEUDOPOLYP.
-- STRICTURE ASSOCIATED WITH LARGE LYMPHOID AGGREGATE.
- THIRTEEN LYMPH NODES NEGATIVE FOR MALIGNANCY ( 0 POSITIVE / 13 ).
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

COMMENT:
The sections show patchy transmural inflammation and skip lesions. Submucosal fibrosis is 
present. Focal ulceration and abscess formation is identified. No granulomas are identified. 

The findings are consistent with Crohn's disease.
ILEUM, COLON, ILEO-COLIC RESECTION:
- SEVERE FOCAL ILEITIS WITH ULCERATION AND TRANSMURAL INFLAMMATION.
- BENIGN STRICTURE ASSOCIATED WITH A LARGE LYMPHOID AGGREGATE.
- FIBROUS ADHESION.
- COLON WITHIN NORMAL LIMITS.
- ONE LYMPH NODE NEGATIVE FOR MALIGNANCY ( 0 POSITIVE / 1 ).
- NEGATIVE FOR DYSPLASIA AND NEGATIVE FOR MALIGNANCY.

COMMENT:
The findings are consistent with chronic, active Crohn's disease.

"Indeterminate colitis"

  • "Indeterminate colitis" is a confusing term and should be avoided.[34]

Suggested terminology

  1. IBDU = IBD unclassified.
  2. CUTE = Colitis of uncertain type or etiology.
    • Should be reserved for resection specimens only.


Dysplasia in inflammatory bowel disease

General

Classified as per Riddell et al.:[35][36][37]

  • Negative for dysplasia.
  • Indefinite for dysplasia.
  • Low grade dysplasia.
  • High grade dysplasia.

Notes:

  • GI experts and generalists have similar rates agreement.[36]

Microscopic

Features:[38]

  • Nuclear changes at the surface - key feature.
    • Nuclear hyperchromasia.
    • Nuclear enlargement - ellipsoid or spherical.

Dysplasia-associated lesion or mass

  • Abbreviated DALM.

General

  • Proving invasive malignancy (on histopathologic grounds alone) in the setting of chronic inflammation is difficult.[39]
  • This diagnosis depends on correlation of endoscopy and histopathology - important.[40]
    • Biopsies are usually taken of the lesion and around the base.
  • This diagnosis usually leads to a colectomy.

Gross

  • Endoscopically "suspicious", i.e. endoscopist thinks this is a DALM - essential feature.
    • Usually have a positive lifting sign.

Microscopic

Features:

DDx:

  • Sporadic adenomatous polyp -- favouring sporadic:
    • Sharp transition between lesion and the surrounding tissue.[40]
    • Polyps not at site of active disease.[41]

Image:

Pouchitis

General

  • Inflammation of an ileal pouch; pouches are a treatment for ulcerative colitis.
    • Generally, pouches are not used in Crohn's disease.
  • Chronic pouchitis seen in approximately 15% of patients.[42]
  • May be assessed by fecal calprotectin.[43]
  • Considered a clinico-pathologic diagnosis.[44][42]

Microscopic

Features:[45]

  • Neutrophils.
  • +/-Crypt abscess - indicator of moderate or severe.
  • Ulceration.

Image:

Scoring system

Pouchitis disease activity index (PDAI) - based on clinical and pathologic factors:

  • Active pouchitis >= 7.
  • Remission < 7.

The histologic component of the PDAI:[45]

  • Neutrophils.
    • Mild.
    • Moderate - crypt abscesses.
    • Severe - crypt abscesses.
  • Ulceration per LPF (mean).
    • <25%.
    • 25-50%.
    • >50.

See also

References

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  2. URL: http://www.gihealthfoundation.org/library/ppts/postcolectomypatient.pdf. 3 March 2011.
  3. 3.0 3.1 Claessen, MM.; Siersema, PD.; Vleggaar, FP. (Apr 2011). "IBD-related carcinoma.". Best Pract Res Clin Gastroenterol 25 Suppl 1: S27-38. doi:10.1016/S1521-6918(11)70007-5. PMID 21640928.
  4. Vos, AC.; Bakkal, N.; Minnee, RC.; Casparie, MK.; de Jong, DJ.; Dijkstra, G.; Stokkers, P.; van Bodegraven, AA. et al. (Sep 2011). "Risk of malignant lymphoma in patients with inflammatory bowel diseases: A Dutch nationwide study.". Inflamm Bowel Dis 17 (9): 1837-1845. doi:10.1002/ibd.21582. PMID 21830262.
  5. Online 'Mendelian Inheritance in Man' (OMIM) 605956
  6. Alvarez-Lobos M, Arostegui JI, Sans M, et al. (November 2005). "Crohn's disease patients carrying Nod2/CARD15 gene variants have an increased and early need for first surgery due to stricturing disease and higher rate of surgical recurrence". Ann. Surg. 242 (5): 693–700. PMC 1409853. PMID 16244543. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1409853/.
  7. Panaccione, R. (Apr 2006). "The approach to dysplasia surveillance in inflammatory bowel disease.". Can J Gastroenterol 20 (4): 251-3. PMC 2659899. PMID 16609751. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659899/.
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  9. 9.0 9.1 9.2 9.3 9.4 9.5 Kirsch, R. 13 December 2010.
  10. "Pathology of ulcerative colitis". http://www.histopathology-india.net/UlCol.htm. Retrieved 17 January 2011.
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  15. 15.0 15.1 Gupta RB, Harpaz N, Itzkowitz S, et al. (October 2007). "Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study". Gastroenterology 133 (4): 1099–105; quiz 1340–1. doi:10.1053/j.gastro.2007.08.001. PMC 2175077. PMID 17919486. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2175077/.
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  18. Mahadeva, U.; Martin, JP.; Patel, NK.; Price, AB. (Jul 2002). "Granulomatous ulcerative colitis: a re-appraisal of the mucosal granuloma in the distinction of Crohn's disease from ulcerative colitis.". Histopathology 41 (1): 50-5. PMID 12121237.
  19. Lin J, McKenna BJ, Appelman HD (November 2010). "Morphologic findings in upper gastrointestinal biopsies of patients with ulcerative colitis: a controlled study". Am. J. Surg. Pathol. 34 (11): 1672–7. doi:10.1097/PAS.0b013e3181f3de93. PMID 20962621.
  20. Beaugerie, L.; Sokol, H. (Aug 2009). "Appendicitis, not appendectomy, is protective against ulcerative colitis, both in the general population and first-degree relatives of patients with IBD.". Inflamm Bowel Dis. doi:10.1002/ibd.21064. PMID 19685454.
  21. 21.0 21.1 Timmer, A.; Obermeier, F. (2009). "Reduced risk of ulcerative colitis after appendicectomy.". BMJ 338: b225. PMID 19273505.
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