Download All That Flattens Is Not Sprue

Small Bowel Biopsy Interpretation
All That Flattens Is Not Sprue
Rhonda K. Yantiss, M.D.
Associate Professor of Pathology and Laboratory Medicine
Weill Cornell Medical College, New York, NY
Challenges to Biopsy Interpretation
Inadequate knowledge of clinical question
Not enough, if any, clinical information


– R/O sprue, abdominal pain
Lack of tissue orientation
Small biopsy or too few tissue fragments
Difficulty understanding spectrum of normal
findings
Extensive differential diagnosis for non-specific
findings
Understanding clinical implications of diagnoses


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
Who Gets a Small Bowel (Duodenal) Biopsy?

Diarrhea
– With or without malabsorption




Iron deficiency anemia
Abdominal pain
GI hemorrhage
Immunodeficiency
– HIV, bone marrow/solid organ transplant, others


Inflammatory bowel disease
Anyone getting upper endoscopy
– Reflux, gastritis, H. pylori, post-operative stomach
1
What is the Clinician Expecting?
Duodenal Biopsies
Diarrhea


– Nothing
– Celiac disease
– Inflammatory bowel
disease
– Autoimmune enteropathy
– Infection
– Tropical sprue
– Drug reaction
– Eosinphilic gastroenteritis
Abdominal pain
–
–
–
–
Nothing
Drug injury (NSAIDs)
Peptic ulceration
Eosinophilic
gastroenteritis
– Neoplasia
– Gastric or esophageal
pathology
What is the Clinician Expecting?
Duodenal Biopsies
Inflammatory bowel
disease

– Involvement by
Crohn’s disease
– Other diseases (H.
pylori)
– Ulcerative colitis

Occasional upper GI
involvement

Immunodeficiency
– Chemotherapy/radiotherapy
– Graft versus host disease
– Post transplant
lymphoproliferative disease
– Opportunistic infection
– Common variable
immunodeficiency



Giardia
Lymphoid hyperplasia
Sprue-like changes
Adequate Clinical Information

Close communication and working
relationship with clinicians
– Common use of language for improved
understanding



Knowledge of serologic study results
Ideally receive endoscopy reports with
images
Background clinical information
– Requisition doesn’t hold all the information
2
37 year-old female with Candidal esophagitis
and nodular duodenum
3
Chronic duodenitis with partial villous
shortening and increased intraepithelial
lymphocytes
Differential diagnosis: celiac disease, immunemediated disorders, infection, and medication
Subsequent Conference Review
At which time the gastroenterologist said, “Well you know the
patient has HIV and AIDS. I thought you would guess that
when I told you that she had Candidal esophagitis” (which, by
the way, he didn’t biopsy).
4
Adequate Tissue Sample

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Three to four intact well-oriented villi in
a row
Avoid stripped villi
Poorly oriented villi may look blunted
Oriented samples on mesh or filter
Must include samples distal to duodenal
bulb
Normal Duodenal Histology



Normal villous:crypt
height ratio is 3-5:1
Easily identifiable
goblet cells and
Paneth cells
One or two mitotic
figures per crypt
Normal Duodenal Histology

Lamina propria
elements
–
–
–
–
Lymphocytes
Plasma cells
Macrophages
Eosinophils

Acceptable as long as
they are not in epithelium
– Neutrophils

Acceptable as long as
they are not in epithelium
5
Normal Duodenal Histology


Absorptive cells and
goblet cells in villi
and crypts
Approximately 25
lymphocytes per
100 epithelial cells
– More numerous on
sides of villi with
relative sparing of
tips
Normal Jejunal Histology
Similar to duodenum, but villi tend to be slightly broader at tips
Normal Ileal Histology
Villi tend to be taller, goblet cells more numerous
6
Normal Ileal Histology
Villi blunted overlying Peyer’s patches, which are normal
Normal Ileal Histology
Intraepithelial inflammation over Peyer’s patches is also normal
Small Bowel Biopsy
Artifacts
Loss of muscularis mucosae flattens biopsy and may look like crypt loss
7
Small Bowel Biopsy
Artifacts
Tangential sectioning may mimic villous blunting
Duodenal Bulb Biopsies

Prone to difficult interpretation
– Brunner’s gland hyperplasia
– Heterotopias
– Peptic injury is common (up to 80%)
Normal Duodenum with Brunner’s Glands
8
Gastric Heterotopia
Peptic Duodenitis
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

One manifestation of H. pylori infection
H. pylori not seen in duodenum unless
there is extensive mucus cell metaplasia
Villous blunting and intraepithelial
lymphocytosis
– Excess of neutrophils
– Numerous Brunner’s glands
– Gastric mucus cell metaplasia on surface
Peptic Duodenitis
9
Peptic Duodenitis
Peptic Duodenitis
Peptic Duodenitis
10
Summary


Small bowel histology is site dependent
Small bowel biopsies vary across populations
– Pediatric biopsies show more crypt crowding and
more goblet cells
– Villous height varies with geography
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Shorter in patients from the tropics
Brunner’s glands and lymphoid follicles cause
villous blunting, but are normal
Artifacts simulate enteritis and villous
abnormalities
Most findings in duodenal bulb biopsies are
clinically inconsequential
Classification of Small Bowel Biopsies

Villous architecture
– Normal
– Variably or moderately blunted
– Severe villous shortening (flat biopsy)

Other specific diagnostic features
– Increased inflammation (amount and
composition) in lamina propria or epithelium
– Absence of normal elements
– Organisms
Classification of Small Bowel Biopsies
Normal Villi
Mild to Moderate
Villous Abnormalities
Peptic duodenitis
X
X
Celiac disease
X
Disease
Severe Villous
Abnormalities
X
X
Crohn’s disease
X
X
Autoimmune
enteropathy
X
X
Common variable
immunodeficiency
X
X
X
Infection
X
X
X
Drug injury
X
X
X
Chemo/radiation
X
X
X
Protein intolerance
X
X
Bacterial overgrowth
X
X
Eosinophilic enteritis
X
X
Mastocytosis
X
X
11
Evaluation of Small-Intestinal Mucosal Biopsy
Checklist



Architecture
Distribution (diffuse or patchy)
Location of inflammation
– Superficial or deep lamina propria
– Surface, crypts, or both

Nature of inflammation
– Lymphocyte predominant
– Neutrophilic cryptitis

Other abnormal features
– Apoptosis
– Infection (CMV)

Presence of normal elements
– Plasma cells
– Goblet, Paneth, endocrine cells
Classification of Small Bowel Biopsies
Enteritis with severe villous
shortening and crypt hyperplasia
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Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Enteritis with no, or variable villous
shortening and crypt hyperplasia
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
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Peptic injury
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Eosinophilic gastroenteritis
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Celiac Disease
Gluten Sensitive Enteropathy



Typically Caucasian of European descent
Presentation at any age
Diagnosis depends on multiple parameters
– Clinical symptoms



Steatorrhea
Weight loss
Iron deficiency anemia
– Characteristic histology, but not specific


Variable villous shortening with crypt hyperplasia
Increased inflammation with intraepithelial lymphocytes
– Unequivocal symptomatic response to gluten
withdrawal
12
Celiac Disease
Gluten Sensitive Enteropathy

Other criteria necessary for diagnosis
– Positive serologic studies

Anti-gliadin, anti-endomysial, tissue
transglutaminase antibodies
– Genetic analysis

HLA-DQ2/DQ8
Tissue Transglutaminase



Most sensitive and specific (ELISA)
Initially believed to be >90% sensitive and
specific
More recent data suggest 71% sensitive and
65% specific
– Lower in patients with less severe disease
– False positive tests

IBD, PBC, heart disease, autoimmune enteropathy and
immune-mediated disorders
– IgA deficiency may lead to false negative result
Histologic Features of Celiac Disease
Complete Villous Shortening
13
Histologic Features of Celiac Disease
Partial Villous Shortening
Histologic Features of Celiac Disease
Crypt Hyperplasia
Histologic Features of Celiac Disease
Intraepithelial Lymphocytes
14
Increased Intraepithelial Lymphocytes with
Normal Villous Architecture
Increased Intraepithelial Lymphocytes with
Normal Villous Architecture
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
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More than 6-40/100 enterocytes
Up to 2.5% of all duodenal biopsies
Differential diagnosis
– Possibly a manifestation of celiac disease
– First degree relatives of celiac patients
– Latent celiac disease

–
–
–
–
–
–
–
Genetic and serologic evidence of gluten sensitivity, but minimal
histologic abnormalities
Peptic injury
NSAIDS
Non-gluten food allergy
Infections
Inflammatory bowel disease, microscopic colitis
Autoimmune diseases
Autism with or without lactose intolerance
Classification of Small Bowel Biopsies
Enteritis with severe villous
shortening and crypt hyperplasia
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
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Enteritis with no, or variable villous
shortening and crypt hyperplasia
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Peptic injury
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Eosinophilic gastroenteritis
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
15
Differential Diagnosis of Celiac Disease
Refractory Sprue


Incomplete, or failed, response to gluten
withdrawal
Possible etiologies
– Non-compliance
– Development of lymphoma
– Other associated diseases (lymphocytosis
elsewhere in the GI tract)
– Collagenous sprue
Celiac Disease-Associated Conditions
Colonic Lymphocytosis/Lymphocytic Colitis
Celiac Disease-Associated Conditions
Collagenous Colitis
16
Celiac Disease-Associated Conditions
Ileal Lymphocytosis
Celiac Disease-Associated Conditions
Lymphocytic Gastritis
Differential Diagnosis of Celiac Disease
Collagenous Sprue
17
Differential Diagnosis of Celiac Disease
Collagenous Sprue
Classification of Small Bowel Biopsies
Enteritis with severe villous
shortening and crypt hyperplasia
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




Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Enteritis with no, or variable villous
shortening and crypt hyperplasia












Peptic injury
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Eosinophilic gastroenteritis
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Differential Diagnosis of Celiac Disease
Crohn’s Disease

Simulates celiac disease
– Increased intraepithelial lymphocytes
– Villous blunting

Other features typical of Crohn’s
disease
– Ulcers
– Active enteritis
– Granulomas and giant cells
– Metaplasia
18
Differential Diagnosis of Celiac Disease
Crohn’s Disease
Differential Diagnosis of Celiac Disease
Crohn’s Disease
Duodenal Involvement by Ulcerative Colitis
19
Duodenal Involvement by Ulcerative Colitis
Classification of Small Bowel Biopsies
Enteritis with severe villous
shortening and crypt hyperplasia

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






Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Infection
Chemo/radiotherapy
Medications
Protein intolerance
Bacterial overgrowth
Enteritis with no, or variable villous
shortening and crypt hyperplasia












Peptic injury
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Infection
Eosinophilic gastroenteritis
Chemo/radiotherapy
Medications
Protein intolerance
Bacterial overgrowth
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy

Clinical features
– Severe protracted diarrhea
– Extra-intestinal immune-mediated disease

No response to gluten withdrawal
– Autoantibodies to enterocytes and goblet cells
– More common in young children

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Sporadic
Immunodysregulation, polyendocrinopathy and
enteropathy, X-linked (IPEX) syndrome
Males>females
Antibodies to enterocytes, goblet cells, parietal cells, islet
cells, tubular basement membrane, ANA, ASMA, anti-DNA
20
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy

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
Rare in adults (<30 reported cases), but
probably under-recognized
Males = females
Mean age: 55 years
10-15% lack autoantibodies to gut epithelium
>80% have other autoimmune disease (renal,
thyroid, hepatic, vasculitis, arthritis, diabetes)
– 1/3 with elevated tissue transglutaminase antibodies
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy
21
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy
Chromogranin
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy
Chronic gastritis
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy
Chronic gastritis
22
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy
Chronic colitis
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy
Pathogenesis unknown

– IgG autoantibodies directed against enterocyte brush
border by indirect immunofluorescence
– Antibody titers decline with immunosuppressive
treatment and remission
– Not clear whether pathogenic or marker of disease
activity
IPEX syndrome related to FOXP3 mutation on X
chromosome

– Modulator of T cell function expressed on regulatory
T cells
– Loss results in “hyperimmunity”
Differential Diagnosis of Celiac Disease
Autoimmune Enteropathy

Treatment
– High mortality if untreated
– Steroids and dietary modification don’t work
– Combination steroids and azathioprine or
cyclophosphamide
– Maintenance with cyclosporine, sirolimus, or
tacrolimus
– Bone marrow/stem cell transplant for IPEX
syndrome
23
Classification of Small Bowel Biopsies
Enteritis with severe villous
shortening and crypt hyperplasia
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth










Enteritis with no, or variable villous
shortening and crypt hyperplasia












Peptic injury
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Eosinophilic gastroenteritis
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Differential Diagnosis of Celiac Disease
Common Variable Immunodeficiency






Immunodeficiency resulting from failed plasma cell
maturation
Symptoms of malabsorption
Chronic giardiasis
Several patterns of injury that mimic celiac disease
and inflammatory bowel disease
Absent, or markedly decreased, plasma cells
May involve the entire gut, simulating inflammatory
bowel disease
Differential Diagnosis of Celiac Disease
Common Variable Immunodeficiency
24
Differential Diagnosis of Celiac Disease
Common Variable Immunodeficiency
Differential Diagnosis of Celiac Disease
Common Variable Immunodeficiency
Differential Diagnosis of Celiac Disease
Common Variable Immunodeficiency
25
Differential Diagnosis of Celiac Disease
Common Variable Immunodeficiency
Celiac Disease
Autoimmune Enteropathy
Crohn’s Disease
Common Variable Immunodeficiency
Features of Immune-Mediated Small-Intestinal Diseases
Celiac
Disease
Crohn’s
Disease
Autoimmune
Enteropathy
Common Variable
Immunodeficiency
Pediatric and adult patients
+
+
+
+
Malabsorption/diarrhea
+
+
+
+
Weight loss/failure to thrive
+
+
+
+
Other autoimmune disorders
+
+
+
+
HLA-DQ2,
HLA-DQ8
NOD2, TLR4
FOXP3
(IPEX syndrome)
TACI, BAFF, APRIL
Defective immune response to
environmental antigens
Dysregulation of
T cells
Abnormal B Cell
Maturation
Clinical Features
Pathogenesis
Molecular predisposition
Mechanism
Serologic Markers
Anti-tissue transglutaminase
+
<5%
30%
Unreliable
Anti-endomysial IgA antibody
+
+/-
+/-
Unreliable
Anti-gliadin IgG antibody
+
+/-
+/-
Unreliable
30%
40-90%
+/-
Unreliable
50-80%
+/-
Anti-Saccharomyces cerevisiae
Anti-enterocyte antibody
26
Classification of Small Bowel Biopsies
Enteritis with severe villous
shortening and crypt hyperplasia










Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Enteritis with no, or variable villous
shortening and crypt hyperplasia












Peptic injury
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Eosinophilic gastroenteritis
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Eosinophilic Gastroenteritis






75% of patients have peripheral eosinophilia
Negative tissue transglutaminase
No response to gluten withdrawal
Infiltration of one, or more, segments of GI tract,
pancreas, or biliary tree
Villous abnormalities, increased intraepithelial
lymphocytes
Three types
– Mucosa predominant (most common)

Diarrhea, bleeding, malabsorption
– Mural (mucosa may be normal)

Obstruction
– Serosal (mucosa is normal)

Eosinophilic ascites
Eosinophilic Gastroenteritis
Photograph courtesy of Dr. Laura Lamps, University of Arkansas
27
Eosinophilic Gastroenteritis
Systemic Mastocytosis
28
Systemic Mastocytosis
Systemic Mastocytosis
CD117
Classification of Small Bowel Biopsies
Enteritis with severe villous
shortening and crypt hyperplasia










Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Enteritis with no, or variable villous
shortening and crypt hyperplasia












Peptic injury
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Eosinophilic gastroenteritis
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
29
Medication/Treatment-Related Injury

NSAIDs

Mycophenolate

Chemotherapy
– Variable villous injury, intraepithelial lymphocytes
– Moderate to severe injury mimics GVHD
– Variable villous injury with apoptosis and
regeneration

Radiation
– Variable villous injury with regenerative epithelial
changes
Medication/Treatment-Related Injury
Mycophenolate
Medication/Treatment-Related Injury
Mycophenolate
30
Medication/Treatment-Related Injury
Colchicine
Medication/Treatment-Related Injury
Colchicine
Medication/Treatment-Related Injury
Colchicine
31
Classification of Small Bowel Biopsies
Enteritis with severe villous
shortening and crypt hyperplasia










Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Enteritis with no, or variable villous
shortening and crypt hyperplasia












Peptic injury
Celiac disease
Refractory sprue
Inflammatory bowel disease
Autoimmune enteropathy
Common variable
immunodeficiency
Eosinophilic gastroenteritis
Chemo/radiotherapy
Medications
Infection
Protein intolerance
Bacterial overgrowth
Infections Causing Villous Abnormalities

Viruses
– Rotavirus
– Cytomegalovirus
– HIV enteropathy

Protozoans
–
–
–
–

Cyclospora cayetenensis
Cryptosporidia
Cystisospora belli
Microsporidia (now considered a fungus)
Bacteria
– Mycobacteria
– Tropheryma whippelii

Fungus
– Histoplasmosis
– Candida
Cytomegalovirus
32
Cytomegalovirus
Adenovirus
Adenovirus
33
HIV Enteropathy
Protista
Apicomplexa
Conoidasida
Coccidiasina
Eucoccidiorida
Adeleorina
Eimeriorina
Cryptosporidiidae
Eimeriidae
Cryptosporidium
C. parvum
C. hominis
Cyclospora
C. cayetanensis
Sarcocystidae
Cystoisospora
(previously Isospora)
C. belli
Cyclospora cayetenensis
34
Cyclospora cayetenensis
Cyclospora cayetenensis
Cryptosporidium
35
Cycloisospora belli
Images courtesy of Dr. Joel Greenson, University of Michigan
Microsporidia
Microsporidia
36
Microsporidia
Microsporidia
Photo courtesy of Dr. Laura Lamps, University of Arkansas
Macrophages in the Intestine

Differential Diagnosis
– Mycobacteria


Immunocompromised
PAS-D and acid fast positive (MAI)
– Histoplasmosis


Immunocompromised
GMS positive
– Whipple’s disease (Tropheryma whippelli)



Immunocompetent
Older, often males with malabsorptive diarrhea,
arthralgias, CNS symptoms
Acid fast negative and PAS-D positive
37
Mycobacterium Avium Intracellulare
Mycobacterium Avium Intracellulare
Histoplasmosis
38
Trophyrema whippelii
Trophyrema whippelii
Trophyrema whippelii
39
Clinical Impact of Pathologic Diagnosis

Celiac disease

Infection

Allergy
– Gluten free diet

Crohn’s disease
– Steroids, ASA
compounds,
immunomodulators,
biologics (anti-TNF)

Autoimmune
enteropathy
– Antibiotics
– Removal of dietary
protein
– Steroids

– Immunosuppression
– Steroids
– Immunosuppression

Common variable
immunodeficiency
– Antibiotics
Graft versus host
disease

Chemo/radiation injury
– Supportive care
On Reporting

Duodenum, biopsy:
– Duodenal mucosa with normal villous
architecture and increased intraepithelial
lymphocytes
Note: Possible etiologies include gluten
sensitivity, immune-mediated injury,
medications (NSAIDs), and infection.
Recommend serologies if patient has signs
or symptoms of malabsorption.
On Reporting

Duodenum, biopsy:
– Chronic duodenitis with marked villous
shortening, crypt hyperplasia, and
increased intraepithelial lymphocytes
Note: Most likely etiology is gluten sensitivity,
although differential includes immunemediated injury, medications, and infection.
Recommend serologies for confirmation.
40
On Reporting

Duodenum, biopsy:
– Chronic duodenitis with partial villous
shortening, crypt hyperplasia, and
increased intraepithelial lymphocytes
Note: Possible etiologies include gluten
sensitivity, immune-mediated injury,
medications, and infection.

Evaluate for specific features and
suggest ancillary tests
Helpful Features and Ancillary Tests
Disease
Histologic Feature
Ancillary Study
Peptic duodenitis
Neutrophils, metaplasia
H. pylori
Celiac disease
Diffuse, superficial
inflammation with IELs
TTG, gliadin, endomysial
antibodies
Crohn’s disease
Neutrophils, metaplasia, ulcers
Small bowel follow through
Autoimmune
enteropathy
Neutrophils, but no goblet cells, Autoantibodies to goblet
endocrine cells, Paneth cells,
cells and enterocytes
Common variable
immunodeficiency
Lymphoid nodules, giardiasis,
CMV, decreased plasma cells
Immunodeficiency and
immunoglobulins
Eosinophilic enteritis
Mixed inflammation with
eosinophils
Peripheral eosinophilia,
history of atopy
Viral enteritis
Disproportionate epithelial cell
injury relative to inflammation,
apoptosis, inclusions
Low threshold for
immunostains
Medication effect
Infection
Organisms often present
Giemsa, gram, GMS
Small Bowel Biopsy Interpretation
Summary
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Try to ensure adequate specimen
Clinical and laboratory information
Understand spectrum of normal
Be aware of extensive differential
diagnosis
Know the clinical implications of
diagnoses
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