Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
Pathology Associates Of Lexington, P.A.
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        Small intestinal Disease
      

[on-line endoscopic atlas]
  • Normal histology:
    1. villous architecture: 
      • shallow biopsy artifact: villi appear shorter and blunter when biopsy does not include lamina muscularis2.
      • Brunner's gland or normal mucosal lymphoid nodule artifact: shorter, blunter villi over these glands or a lymphoid nodule normally2.
      • normal: slender to leaf-shaped; not all straight; Rubin dictum is "four or more normal villi in any step-cut of a biopsy means villi are normal" 2, 13 ...but, see below.
      • Cyrus E. Rubin villous architectural abnormality classification, below2.
    2. surface/lumenal epithelium compartment:
      • epithelial cells: single-cell layer of tall absorptive columnar cells with brush borders which line villi; small oval nuclei; occasional goblet cells.  Disaccharidase deficiency diarrhea and malabsorption are reflected in quantity loss of the brush border in actuality or by villous atrophy7. Epithelial nuclei orderly in basal position and stratify when injury occurring13. IHC for CD10 decorates the intact brush border nicely. Lipid vacuolation of enterocytes may reflect a-beta lipoproteinemia.
      • Peptic duodenopathy (hyperacidic duodenopathy): prolonged gastric hyper-acidity can affect proximal duodenum & cause foveolar metaplasia of the acid-injured absorptive epithelium of duodenum. Can see increased volume of Brunner's gland component (if biospies deep enough to visualize) often expressed by findings of glandularity high in lamina propria [L08-13463; S09-4458]; may even see extension of antral glandularity even with a few parietal cells [L09-11085]. When relatively acute & intense, the foveolar areas can undergo reactive gastropathy change [S09-4458].
      • duodenal "villous-tip score" (VTS)...intraepithelial lymphocytes :

        IELs are normally in a "decrescendo pattern" of decreasing concentration from crypt to tip...hence the development of the VTS. Since increased IELs are associated with other than just gluten sensitivity, maybe we should speak in terms of IEL evidence of "cell-mediated sensitivity enteropathy" (a term more all-inclusive than "protein sensitive enteropathy (PSE)". Rule of thumb H&E normal for IEL concentration is 1 IEL per 5 epithelial cells (about 4 per 20)13. Normal (EGD for GERD) controls H&E IEL "villous tip score" MEAN in the duodenum is 2.2 per 20 TIP epithelials (range 0.8-5.4); cases that were clinically suspect for gluten sensitive enteropathy (GSE) which turned out to not be GSE, 4.3 per 20 (range 0.4-11) [could they have been some other PSE?]; and GSE is 11.6 per 20 (range 3-22.8)5.

        Amplification Note: In order to enhance the "recognition factor" of IELs, we began using IHC CD3 (or LCA) "signal amplification"..."CD3-amplified VTS". Count CD3-tagged IELs per 20 villous-surface epithelial enterocytes in at least 5 random villous tips (do 10 tips if possible) and calculate an IELs per 20 epithelials per-tip average; and I'd offer that it doubles the perception (counting liberally) of IELs so that normal is surely up to 4 IELs per 20 epithelials/enterocytes; 5-9 is of uncertain significance ("protein sensitivity enteropathy not ruled out"); and 10 or higher is "evidence of protein sensitivity enteropathy". GSE can be early enough that a normal CD3-amp-VTS of 5-6 might still have symptoms disappear on a gluten reduced diet [S05-3671, a physician].

      • duodenal "IEL distribution pattern": the diffuse...from crypt to tip...pattern of increased IELs has the highest association with elevated GSE-associated serum antibodies5 (where-as...see above...the decrescendo pattern is normal).
      • IHC stain for LCA (CD3 even better) makes IELs much easier to see because lights up cytoplasm...(can only note as IELs by seeing a nucleus on H&E)!
      • normal jejunal (duodenal?) IEL is 1 intraepithelial lymphocyte (IEL) for every 5 epithelials2,3; 13/100 (.65/5) in ileum3; 2-4/10 (1-2/5) small bowel epithelials6.
      • IELs are T cells (probably suppressor) and tend to accumulate in the layer/zone containing the epithelial nuclei and may reflect a local immune response of reaction to epithelial cells by infection or foreign antigens & they are not shed into the gut3.
      • mitoses only in the short intramucosal crypt of Lieberkuhn region, normally.
      • crypts contain Paneth cells and occasional endocrine cells and sit on the lamina muscularis.
      • macrophages and mast cells are occasionally found within the surface epithelium, while polys and eosinophiles are quite unusual except in inflammatory states; Whipple's disease has increased intraepithelial eosinophiles, polys, and macrophages3; a case [S-02-3956] subsequently found to be eosinophilic gastroenteritis had very mild eosinophilic exocytosis.
    3. epithelial-collagen table interface:
      • apoptosis material:
        • autoimmune enteropathy: IFA serology testing is positive for IgG linear enterocyte apical zone deposits.
    4. collagen table: if any evidence of thickening, it could indicate collagenous duodenitis [S08-4826].
    5. lamina propria content:
      • plasma cells: most common, followed by lymphs (round cell content normally varies by country of origin due to genetic & dietary differences)2.
      • rare lymphoid nodule is OK.
      • macrophages with debris inclusions occasionally at villous tips.
      • eosinophiles frequently present & do not imply "food allergic enteropathy"16. Eosinophilic esophagitis (EE) is the best described of the eosinophilic gastrointestinal diseases (EGIDs)16. Eosinophilic gastroenteritis (EGE) indicates involvement of small bowel.
      • poly: only a RARE poly is tolerated as normal.
      • mast cells: lamina propria has about 13 per 40x hpf & >20 is abnormal, with a diffuse increase (without sheets or nodules) possibly indicating the sort of "functional" entity of "mastocytic enterocolitis" which is not associated with cutaneous or systemic mastocytosis (which, when involving intestine, is likely top be H&E visible with sheets & nodules) and does not have elevated serum tryptase17.
      • eosinophilic deposits: amyloid or para-amyloid; collagenous sprue [S08-4826]; ischemic effect can cause an eosinophilic "look " having to do with fibrin deposition & collagenization.
      • hemorrhagic enteropathy: this may be freshly present as b lood in lamina propria as mechanical artifact of the endoscopic process and/or a result of intentional (prescribed) or unintentional anticoagulation or antiplatelet therapy [S09-2262].
      • lacteals: abnormality suggested if more than 1 & truly dilated so as to make villous profile enlarged & likely represent tumor obstruction if capillaries also quite dilated [L08-12222].
      • edematous:
        • probably in pellagra malabsorptive diarrhea (pellagra: dermatitis, diarrhea, and dementia due to niacin and/or nicotinamide deficiency...Italian "pelle agra", rough skin).
        • portal hypertensive edema.
        • hereditary angioedema (HAE)...may be documented if biopsied during an attack.
    6. ulcer: may be ASA or NSAID induced [L09-2445]; if terminal ileum, think also of early Crohn's.
    7. submucosa:
      • inflammatory cells: normally negative for infiltrates.
      • Brunner's glands: can increase in the face of chronic gastric hyper-acidity to form plaques and even polyps. Brunner's can have an increased fibromuscular component & the combined glandulomyomatous tissue seem to form a prominent mucosal fold [S09-2805] & with much enlargement to be an adenoma and with enlargement having increased muscle & ducts, a hamartoma [L07-3390, 23 grams & 6 x 3 x 2.5 CM].
      • fibrosis: bypassed segment having a dependent segment secured by adhesions can form a sort of lymphostatic sclerosis.
  • Rubin villous architectural classification of small bowel biopsies2:
    1. "flat biopsy", class 3, severely abnormal: villi almost absent & crypt hyperplasia.
      • nonspecific:
        1. symptomatic celiac (almost all class 3 biopsies in North America are due to GSE13).
        2. other protein injury (milk, soy, chicken, eggs, tuna)13.
        3. some tropical sprue.
        4. childhood kwashiorkor.
        5. refractory sprue.
        6. familial enteropathy.
        7. lymphocytic enterocolitis13.
      • diagnostic:
        1. collagenous sprue (thick collagen table).
        2. late onset immunodeficiency (common variable hypogammaglobulinemia...CVH)  (essentially absent plasma cells and presence of lymphoid nodules).
    2. "variably abnormal villi", class 2, moderately abnormal (focal severe villus abnormallity13): overall broadened and shortened villi:
      • nonspecific:
        1. subclinical celiac [S-03-5048].
        2. other protein allergies13.
        3. 25% of dermatitis herpetiformis cases
        4. infectious gastroenteritis13.
        5. stasis (bacterial overgrowth) syndromes13.
        6. some tropical sprue (rare13).
        7. mucosal geographic variation.
        8. infectious gastroenteritis13.
        9. systemic mastocytosis13.
        10. autoimmune enteropathy13.
        11. Torkelson syndrome13.
        12. Crohn's disease13.
        13. nonspecific duodenitis13.
        14. Zollinger-Ellison (ZE or Z-E) syndrome13.
        15. graft versus host (GVH) disease.
      • diagnostic:
        1. Whipple's disease13.
        2. immunodeficiency syndromes (not AIDS)13.
        3. eosinophilic gastroenteritis (high concentrations of eosinophiles in mucosa or submucosa13).
        4. parasitic13, fungal, viral diseases.
        5. M. avium intracellulari complex infection13.
        6. primary intestinal lymphoma (enteropathy associated T-cell lymphoma and/or "ulcerative jejunoileitis ["diffuse ulceration of jejunum and ileum", "chronic ulcerative nongranulomatous jejunoileitis", "idiopathic chronic ulcerative enteritis", "malignant histiocytosis", or epitheliotropic lymphoma of small bowel"]")13.
        7. Waldenstroms macroglobulinemia13 [L-06-10703].
        8. abetalipoproteinemia (enterocyte vacuolation)13.
        9. acrodermatitis enteropathica (rod like inclusions in Paneth cells by EM)13.
        10. tufting enteropathy (focal surface epithelial crowding, disorganization, and tufting)13.
        11. lymphangiectasia, primary or secondary13.
        12. late onset immunodeficiency (common variable hypogammaglobulinemia...CVH)  (essentially absent plasma cells and presence of lymphoid nodules).
        13. severe B12 or folate deficiency (includes crypt hypoplasia).
        14. those malnourished to the point of marasmus and kwashiorkor (includes crypt hypoplasia).
        15. secondary to radiation and/or chemotherapy (includes crypt hypoplasia).
        16. microvillus inclusion (in infants) disease (includes crypt hypoplasia...and the inclusions may be visible with PAS or CEA stains).
    3. "normal villi", class 1, mildly abnormal: many villi branched, broadened, or fused above the crypts, mildly shortened [V:T ratio < 3:1]:
      • diagnostic:
        1. abetalipoproteinemia: absorptive cells loaded with fat vacuoles.
        2. Crohn's disease.
        3. X-linked immunodeficiency (essentially absent plasma cells ).
        4. lipid storage disease: vacuolated ganglion cells, capillaries & macrophages.
        5. amyloidosis.
        6. chronic granulomatous disease: pigmented, vacuolated lam. propria macrophages.
        7. melanosis: lam. propria melanosis macrophages.
  • Parasitic:    
  • Bacterial:
    1. bacterial overgrowth syndrome clinically mimics celiac disease malabsorption.
  • Viral:
  • Non-infectious:
    1. celiac disease (gluten sensitivity or gluten sensitive enteropathy...GS/GSE...one of the group of PSEs) :
      • associated antibody serology: often positive for gliadin and endomysial Abs as IFA tests  (or tTG as ELISA test)...significant false positive rate5. And, antibody titers often don't elevate prior to some real villous injury15. So, if IELs are increased but serology is negative, yet it is clinically c/w GSE: (1) do a trial of dietary gluten restriction; or, (2) dietary challenge with gluten-rich diet and re-biopsy to see if a real increase in IELs15. If responses not compatible with GSE, then may be some other PSE, see below.
      • notes [another outline]:
        • of people biopsied because GSE was a possibility, 38% turn out to have IBS (irritable bowel syndrome) and 18% have dyspepsia only5.
        • even GSE cases with Marsh stage IV biopsies can be asymptomatic if only a short length of gut is involved5.
        • of those GSE cases with normal villous architecture, only 80% had anti-IgA-endomysial antibody positivity and 50% had anti-IgA-gliadin antibody positivity & of the suspected GSE cases finally proven not to be GSE (non-GSE cases), the false positive serology rate was 5% for anti-endomysial and 20% for anti-gliadin  5.
        • in GSE-suspect cases, BIOPSY likely most sensitive parameter to see who to give a real gluten-free diet trial to cinch or refute the diagnosis of G-S syndrome.5.
        • full-blown celiac sprue has steato-diarrhea, malabsorption, weight loss and malnutrition5.
        • nonclassic manifestations (20-50% of gluten sensitive patients) are microcytic (iron deficiency) anemia, folate deficiency, mild diarrhea, flatulence, loose stools, and severe osteoporosis5; peripheral neuropathy (paresthesias & sensory abnormalities), and muscle weakness with proximal myopathy9.
        • prevalence of GSE is about 1 in 120-3008 North Americans (up to 1%) USA Caucasians, and [as with hemochromatosis] thought to be markedly underdiagnosed5.
        • the histological alterations are the typical pattern of  suppressor T cell-mediated injury; and, in the GS cases with increased IELs, those IELs are positive for T-cell receptor gamma/delta sites (marker not yet available by IHC for paraffin embedded tissue%5 (see above for more about IEL counts and below about conditions with increased IELs).
        • the gliadin fraction of wheat gluten and the alcohol-soluble prolamins of other grains are the extrinsic food factor leading to the intestinal damage13.
        • synonyms for the situation of Marsh stage 0 & 1: subclinical celiac sprue, silent celiac sprue, gluten-sensitive disease with mild enteropathy, low-grade enteropathy, latent celiac sprue, minimally symptomatic enteropathy, minimally symptomatic celiac sprue, high-density IEL enteropathy, and potential celiac disease.
      • spectrum (Rubin stages, above; histological...Marsh stages12, 14 and two modifications, as follows) of gluten-sensitivity mucosal change1:
        1. Marsh stage 0, pre-infiltrative:
          • H&E normal.
          • LCA/CD3 should show mild increase in intraepithelial lymphs (IELs) [a VTS, say, 5-10].
          • lamina propria normal to borderline cellular.
          • or, histology is normal on rebiopsy post gluten-free diet.
        2. Marsh stage 1, infiltrative (lymphocytic enteritis) :
          • often looks normal on H&E.
          • normal mucosal architecture with about a 10:1 to 5:1 ratio of absorptive villous height to crypt length (normal distal duodenal 3:1-5:111); may begin to see absorptive cell "injury effect". 
          • H&E IELs markedly increased = to > 30 IELs per 100 epithelials12.
          • LCA (CD3) stain highlights intraepithelial ("infiltrative") lymphocytes & a VTS of, say, 10-25 (can't really do a VTS above about 25)  [S-01-6591; S-01-7901; S-01-8348, S-01-9377; L03-135 VTS 26]
          • lamina propria normal to borderline/mildly cellular.
          • seen in early evolution of celiac disease, some patients with dermatitis herpetiformis (DH), and in some first-degree relatives (asymptomatic) of patients with celiac sprue.
        3. Marsh stage 2, hyperplastic:
          • crypt epithelium begins to increase up the villi at the expense of decreasing goblet and absorptive epithelium, & with increased mitoses, which should clearly show some "injury effect" (ratio decreases)[S-01-10570; S-03-5048; LMC-05-3268].
          • intraepithelial lymphocytes in absorptive and crypt epithelium.
          • lamina propria: increasing cellularity.
          • this lesion seen in about 20% of untreated DH patients.
        4. Marsh stage 3, destructive:
          • villous flattening becoming appreciable.
          • lamina propria: increased cellularity.
          • Marsh-Oberhuber14 grading uses 3 subgroups of Marsh 3 and some prefer M-H &, therefore, don't speak of a Marsh 412. The 3 subgroups are as to atrophy: 3a=mild/partial, 3b=marked/subtotal, or 3c=complete/total villous atrophy.
        5. Marsh stage 4, atrophic:
          • flat mucosa (if not paying close attention one might see lack of increased VTS & miss that villi are actually flattened and not just maloriented in histological embedding [S08-15468].
          • GSE and some other protein intolerance (chicken, soy, tuna, milk, and eggs) are all said capable of causing flat mucosa13.
          • lamina propria: increased cellularity.
        6. Simple grading proposed 200514:
          1. grade A: no atrophy.
          2. grade B: has atrophy
            • B1: villous to crypt ratio reduced to 3:1 with still detectible villi.
            • B2: villi no longer detected.
    2. celiac mimics...differential diagnosis of both "cell mediated sensitivity enteropathy"...increased (see normal range, above) small bowel IELs & otherwise similar:
      • Protein sensitivity enteropathy (PSE):
        • celiac disease, gluten sensitive enteropathy (GSE),  which responds to treatment.
        • celiac disease, gluten sensitive enteropathy,  which does not respond and is variously referred to as refractory sprue, refractory celiac disease, refractory gluten sensitivity, or idiopathic lymphocytic enteritis4.
        • dermatitis herpetiformis patients4 and their first degree kin (skin manifesting celiac disease ?).
        • rice or cereals 15.
        • cows milk protein intolerance mimics celiac clinically & histologically13.
        • soy protein intolerance mimics celiac clinically & histologically13.
        • tuna protein intolerance mimics celiac clinically & histologically13.
        • egg protein intolerance mimics celiac clinically & histologically13.
        • chicken protein intolerance2 mimics celiac clinically & histologically13.
        • Helicobacter gastritis [S09-11502].
      • colonopathy associated increased IELs:
        • "lymphoplasmacytic enteropathy" associated with 40% of collagenous colitis cases: mimics celiac histology [S07-9902]) but negative serology.
        • lymphocytic enterocolitis: GSE-like enteric villus lymphocytosis associated with a lymphocytic colitis like colonic epithelial lymphocytosis & found to be refractory to gluten withdrawal13.
        • in association with other chronic colitis cases.
      • Organism associated increased IELs:
        • tropical sprue; Giardiasis in children3.
        • in AIDS cases having microsporidial enteropathy3.
        • other infections: giardia or cryptosporidium parasitic infections; gastric helicobacter infection [S-06-11237]; enteric bacterial overgrowth conditions; viral enteritis; nontropical sprue15.
        • in association with a variety of autoimmune diseases (biopsy has reduced plasma cells & may have lymphoid follicles & parasites)15.
      • Immunodeficiency associated cases:
        • immunodeficiency syndromes mimic celiac histology except no plasma cells4.
        • selective IgA deficiency4.
        • in autoimmune enteropathy (usually in pediatric age group)15.
      • Other:
        • eosinophilic gastroenteritis mimics celiac malabsorption clinically.
        • diffuse small-cell lymphoma mimics celiac histology4.
        • children with autism (whether or not lactose deficient)15.
        • intuitive suspicion that some medications (such as NSAIDs) can cause15.
    3. regional enteritis (Crohn's disease):
    4. portal hypertensive enteropathy:
    5. hereditary angioedema: another affliction (severe N&V and acute abd. pain & diarrhea) of the intestines associated with skin lesions (dermatitis herpetiformis & celiac another) & due to a defect in the gene that controls a blood protein called C1-esterase inhibitor. The genetic defect results in production of either inadequate (85% of cases...detected by quantitative assay) or nonfunctioning C1-esterase inhibitor protein (15% of cases...detected by functional assay). An HAE website HERE.
    6. dysfunctional gallbladder (GB)diarrhea syndromes: "bile salt diarrhea"
      • postcholecystectomy diarrhea syndrome: about 5% or less of patients having GB removed undergo failure of small bowel to adequately absorb the bile salts in the now-fairly-continually released bile.
      • Habba syndrome: like the above but you have your gallbladder but it fails to uptake & concentrate & then periodically release bile produced by the liver but releases fairly continuously (may affect as many as 3,000,000 Americans)...could be a diseased or otherwise abnormal GB.

References:

  1. Marsh, Michael N., Gluten, Major Histocompatibility Complex, and the Small Intestine..., [special reports and reviews] Gastroenterology 102:330-354, 1992.
  2. Norris, H. T., Contemp. Issues in S. P., vol. 2: Pathology of the Colon, Small Intestine, and Anus, 1983, chapter 6 [W. O. Dobbins, acknowledging the work of Cyrus E. Rubin] [in EBS's office].
  3. Dobbins, W. O., Progress Report: Human Intestinal Intraepithelial Lymphocytes, Gut 27(8):972-985, 1986.
  4. Moskaluk, CA, [editorial] Sailing Past the Horizon: The Histologic Diagnosis of Celiac Disease in "Nonflat" Intestinal Mucosa, AJCP 116(1):7-9, July 2001.
  5. Goldstein, NS and Underhill, J, Morphologic Features Suggestive of Gluten Sensitivity in Architecturally Normal Duodenal Biopsy Specimens,  AJCP 116(1):63-71, July 2001.
  6. Dayharsh & Burgart, of Mayo Clinic Dept. of Surg. Path, CAP Today, page 104, 7/2001
  7. Whitehead [text], 5th Ed. 1997 [EJM's office]
  8. Farrell RJ, Kelly CP, Current Concepts: Celiac Sprue, Review Article, NEJM 346(3):180-187, 17 January 2002.
  9. Tadataka Yamada, Gastroenterology..., 2 vol. text [LMC library]
  10. Silverberg, Surgical Pathology 2 vol. text [BWD's office]
  11. Fenoglio-Preiser CM, GI Path text, 1989 [BWD's office]
  12. Wahab PJ, et. al., AJCP, 118:459-463 [Netherlands group & good photos of Marsh stages]
  13. Petras RE, A Practical Approach to Gastrointestinal pathology: Small Bowel Biopsy Interpretation and Specimen Handling, US & Canadian Academy of Pathology, March 2002 (91st annual meeting) short course handout, 10 pages (online @ USCAP website).
  14. Corazz GR & Villanacci V, "Viewpoint: Coeliac Disease", J. of Clin. Path 58(6):573-574, 2005.
  15. Lauwers GY, et. al., "Intraepithelial Lymphocytosis in Architecturally Preserved Proximal Small Intestinal Mucosa,...", Arch. Path. & Lab. Med. 130:1020-1025, July 2006.
  16. Furuta GT, Children's Hosp. Boston, editorial: "Eructations From Eosinophils", Gastroenterology 131(5):1629-30, November 2006.
  17. Jakate S, et. al, "Mastocytic Enterocolitis: Increased Mucosal Mast Cells in Chronic Intractable Diarrhea", Archives of Pathology and Laboratory Medicine,130(3):362–367, 2006.

(posted 2001; latest addition 27 September 2009)
 
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