Acute gastroenteritis (AGE) affecting the stomach is unlikely to be biopsied. Transferred through the air or by human contact, it comes on suddenly. When afebrile, without fever, without seriously ill feelings and very primarily nausea and vomiting and stomach cramps, it is likely viral; if it includes a touch of feverish feeling or low grade fever plus general aches and pains, folks refer to it as "stomach flu". If diarrhea, it is almost always non-bloody. Notorious in our area in the winter of 2012-13 is the norovirus GII.4 genotype of the various small round-structured viruses (SRSVs). There can also be bacterial causes and causes by other organisms and toxins. A really-ill, sudden onset with higher fever & bloody diarrhea, a bacterial cause comes into the differential diagnosis. AGE can also come from "food poisoning", norovirus being only one cause. Much of the below has to do with work up of less dramatic situations, except for C. diff. colitis workups.
[on-line endoscopic atlas]
epithelial-collagen table interface:
- Normal histology:
H&E normal histology is seen in early-stage protein sensitive enteropathies, stress-related GI complaints, mastocytosis without increased mast cells in the biopsy site, and mast-cell-activation syndrome (MCAS...which is acqired, mostly in females, and common & with symptoms of excessive systemic histamine [17% of Germans])22. Mast cells of MCAS & even early mastocytosis cannot be properly appreciated without IHC marker stains for CD117 and/or CD25 which label mast cells.
artifact: villi appear shorter and blunter when biopsy
does not include lamina muscularis2.
or normal mucosal lymphoid nodule artifact: shorter,
blunter villi over these glands or a lymphoid nodule
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,
- Cyrus E. Rubin villous architectural
abnormality classification, below2.
- 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.
- parasites: (1) Giardia may be seen in mucus attached to the surface. (2) AFB positive Cyclospora (a July 2013 USA out break) may be in the lumenal surface epithelials and be associated with some villus blunting [biopsy changes]. (3) there may be cryptosporidium attached in the microvillous layer, as tiny rounded protrusions [biopsy photo], weakly AFB positive.
- Peptic duodenopathy (PD...hyperacidic duodenopathy): common in USA; prolonged gastric hyper-acidity can affect proximal duodenum & cause increased volume of Brunner's gland component (if biospies deep enough to visualize) often & best expressed by findings of glandularity in lamina propria above the muscularis mucosae [L08-13463; S09-4458; L11-13605]. More prolonged cases may additionally cause foveolar metaplasia of the acid-injured absorptive epithelium of duodenum; more frequently without the associated foveolar metaplasia being demonstrated [L11-13604]; may even see post-pyloric 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]. With usual-type biopsy sampling via EGD, there is a very limited view of mucosa; so, if just mild superficial Brunner's glands are noted, it is best to conservatively offer..."evidence of"...the possible diagnosis (rather than dogmatically "make" the diagnosis of PD).
- question of adenomatous lesion: Uncertainty of an adenomatous quailty can be fortified toward that diagnosis if (1) Ki-67 is claerly quite increased in the suspect cells (2) along with the same cells having nuclear p53 positivity (both markers in claerly increased contrast to adjecent epithelials [L12-2931].
score" (VTS)...intraepithelial lymphocytes : increased IELs might be referred to as "IELosis"21. Protein intolerance of some type manifested by lymphocytosis (IELs). IELs are normally in a "decrescendo pattern" of decreasing concentration from crypt (more there) to tip (less there)...hence the development of the villus tip score (VTS), below. Since cell-mediated type of sensitivity manifests as increased IELs (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)".
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 tip epithelials
average (and I'd offer that IHC doubles the perception
(counting liberally) of IELs so that normal is surely up
to 4 IELs per 20 epithelials/enterocytes19 (one series of 17 cases with CD being ruled out averaged a VTS of 4.619); 5-9 is of uncertain
significance ("protein sensitivity enteropathy not
ruled out")(one series of 19 cases with treated CD averaged 7.919); and 10 or higher is "evidence of
protein sensitivity enteropathy"(one series of 17 cases with CD ruled out averaged 4.619). One series of 11 cases with possible CD (normal villi & positive endomysial antibody) averaged 9.219. 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], especially if biopsies happen to be taken after a period of relative abstinence of dietary intake of the offending agent. And low-level IEL increases may be associated with as-yet-only-weak serological "positivity" of early disease [S11-5422]. In case insurance companies refuse to pay, HERE. Old H&E scoring: Rule of thumb H&E normal for
IEL concentration is 1 IEL per 5 epithelial cells (about
4 per 20)13, 20. 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.
distribution pattern": the diffuse...from
crypt to tip...pattern of increased IELs has the
highest association with elevated celiac/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
(duodenal?) H&E IEL presence is 1 intraepithelial lymphocyte (IEL) for
every 5 epithelials2,3; 13/100 (.65/5)
in ileum3; 2-4/10 (1-2/5) small bowel
- 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.
Paneth cells and occasional endocrine cells and sit on
the lamina muscularis.
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
collagen table: if any evidence of thickening, it could indicate collagenous duodenitis [S08-4826].
lamina propria content:
- apoptosis material:
- autoimmune enteropathy: IFA serology testing is positive for IgG linear enterocyte apical zone deposits.
ulcer: may be ASA or NSAID induced [L09-2445]; if terminal ileum, think also of early Crohn's.
plasma cells: most
common, followed by lymphs (round cell content normally
varies by country of origin due to genetic & dietary differences)2.
lymphoid nodules: rare lymphoid nodule is OK; when numerous & clearly benign by H&E and/or IHC immuno-architecture = "reactive lymphoid enteropathy" [L10-1660 54 y/o female bariatric jejunal segment].
macrophages: (1) with
debris inclusions occasionally seen on H&E at villous tips...doubtful significance. (2) If increased H&E-visible foamy/granular macrophages, check for Whipple disease and MAC [HERE].
present & do not always 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. Protein intolerance may be manifested by eosinophiles.
- polys: 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 blood 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].
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.
- inflammatory cells: normally negative
- 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.
diagnosis of both "cell mediated sensitivity enteropathy"...increased (see normal range, above) small
bowel IELs & otherwise similar; Protein intolerance manifested by lymphocytosis (IELs):
architectural classification of small bowel biopsies2:
class 3, severely abnormal: villi almost absent & crypt
celiac (almost all class 3 biopsies in North America
are due to GSE13).
injury (milk, soy, chicken, eggs, tuna)13.
sprue (thick collagen table).
immunodeficiency (common variable hypogammaglobulinemia...CVH) (essentially
absent plasma cells and presence of lymphoid nodules).
abnormal villi", class 2, moderately abnormal (focal
severe villus abnormallity13): overall
broadened and shortened villi:
25% of dermatitis
(ZE or Z-E) syndrome13.
host (GVH) disease.
syndromes (not AIDS)13.
gastroenteritis (high concentrations of eosinophiles
in mucosa or submucosa13).
fungal, viral diseases.
intracellulari complex infection13.
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.
enteropathica (rod like inclusions in Paneth cells
(focal surface epithelial crowding, disorganization,
primary or secondary13.
immunodeficiency (common variable hypogammaglobulinemia...CVH) (essentially
absent plasma cells and presence of lymphoid nodules).
or folate deficiency (includes crypt hypoplasia).
to the point of marasmus and kwashiorkor (includes
to radiation and/or chemotherapy (includes crypt
inclusion (in infants) disease (includes crypt
hypoplasia...and the inclusions may be visible
with PAS or CEA stains).
class 1, mildly abnormal: many villi branched, broadened,
or fused above the crypts, mildly shortened [V:T ratio < 3:1]:
absorptive cells loaded with fat vacuoles.
immunodeficiency (essentially absent plasma cells
disease: vacuolated ganglion cells, capillaries & macrophages.
disease: pigmented, vacuolated lam. propria macrophages.
lam. propria melanosis macrophages.
overgrowth syndrome clinically mimics celiac disease malabsorption.
- celiac disease (gluten sensitivity or gluten sensitive enteropathy...GS/GSE...one of the group of PSEs); Protein intolerance manifested by lymphocytosis (IELs):
- 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
- of people biopsied
because GSE was a possibility, 38% turn out to
have IBS (irritable bowel syndrome) and 18% have
- 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.
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
- 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
- spectrum (Rubin stages, above; histological...Marsh
stages12, 14 and two modifications, as follows)
of gluten-sensitivity mucosal change1:
- 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.
- Marsh stage 1, infiltrative
(lymphocytic enteritis) :
- often looks normal
- 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
- LCA (CD3) stain highlights
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
- 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
- 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;
- intraepithelial lymphocytes
in absorptive and crypt epithelium.
- lamina propria: increasing
- this lesion seen
in about 20% of untreated DH patients.
- Marsh stage 3, destructive:
- villous flattening
- lamina propria: increased
- 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.
- 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
- lamina propria: increased
- Simple grading proposed 200514:
- grade A: no atrophy.
- grade B: has atrophy
- B1: villous to crypt ratio reduced to 3:1 with still detectible villi.
- B2: villi no longer detected.
regional enteritis (Crohn's disease):
portal hypertensive enteropathy:
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.
dysfunctional gallbladder (GB)diarrhea syndromes: "bile salt diarrhea"
- 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
- 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, S13-1201].
- 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 [biopsy photo] (or cyclospora) 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.
- 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, 20.
Graft versus Host disease (GVH): a marker is epithelial apoptosis & injury can result in acute enteritis or ileitis with ulceration (L12-14036).
- 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.
- Marsh, Michael N., Gluten, Major
Histocompatibility Complex, and the Small Intestine..., [special
reports and reviews] Gastroenterology 102:330-354, 1992.
- 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].
- Dobbins, W. O., Progress Report:
Human Intestinal Intraepithelial Lymphocytes, Gut 27(8):972-985,
- Moskaluk, CA, [editorial] Sailing
Past the Horizon: The Histologic Diagnosis of Celiac Disease
in "Nonflat" Intestinal Mucosa, AJCP 116(1):7-9,
- Goldstein, NS and Underhill, J, Morphologic
Features Suggestive of Gluten Sensitivity in Architecturally
Normal Duodenal Biopsy Specimens, AJCP 116(1):63-71,
- Dayharsh & Burgart, of Mayo Clinic
Dept. of Surg. Path, CAP Today, page 104, 7/2001
- Whitehead [text], 5th Ed. 1997 [EJM's
- Farrell RJ, Kelly CP, Current Concepts:
Celiac Sprue, Review Article, NEJM 346(3):180-187, 17 January
- Tadataka Yamada, Gastroenterology...,
2 vol. text [LMC library]
- Silverberg, Surgical Pathology 2
vol. text [BWD's office]
- Fenoglio-Preiser CM, GI Path text,
1989 [BWD's office]
- Wahab PJ, et. al., AJCP, 118:459-463
[Netherlands group & good photos of Marsh stages]
- 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).
- Corazz GR & Villanacci V, "Viewpoint: Coeliac Disease", J. of Clin. Path 58(6):573-574, 2005.
- Lauwers GY, et. al., "Intraepithelial Lymphocytosis in Architecturally Preserved Proximal Small Intestinal Mucosa,...", Arch. Path. & Lab. Med. 130:1020-1025, July 2006.
- Furuta GT, Children's Hosp. Boston, editorial: "Eructations From Eosinophils", Gastroenterology 131(5):1629-30, November 2006.
- 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.
- Ho-Yen C, et. al., "Recent Advances in refractory coeliac disease: a review", Histopathology 54(7):783-795 (photos clearly showing advantage of counting with CD3), June 2009.
- Biagi F, et. al., "Intraepithelial lymphocytes in the villous tip: do they indicate potential coeliac disease?", J Clin Pathol, 57:835-839, 2004. (the use & advantage of CD3 amplification) .
- Ian Brown, Mari Mino-Kenudson, Vikram Deshpande, and Gregory Y. Lauwers, "Intraepithelial Lymphocytosis in Architecturally Preserved Proximal Small Intestinal Mucosa: An Increasing Diagnostic Problem With a Wide Differential Diagnosis",
Archives of Pathology & Laboratory Medicine, 130(7):1020-1025, July 2006).
- Ensari A, "Gluten-Sensitive Enteropathy (Celiac Disease) Controversies in Diagnosis and Classification ", Arch. Path. & Lab. Med. 134:826-836, June 2010 HERE.
- Jesse Madden, M. D., "The Patient Celiac" website, HERE.
(posted 2001; latest addition 17 April 2015)