Approach to Duodenal Mucosal Biopsies Jeffrey Goldsmith, MD

Approach to
Duodenal Mucosal
Biopsies
Jeffrey Goldsmith, MD
Beth Israel Deaconess Medical Center
Children’s Hospital Boston
Harvard Medical School
Boston, Massachusetts
Outline
 Normal
 Peptic
Duodenitis
 Celiac
Disease
Why Biopsy?
 Peptic
injury
 Other inflammatory disorders
 Malabsorptive conditions
 Infections
 Neoplasms
Normal Duodenal Mucosa:
Things to Remember
 Altered
villous architecture over:
– Lymphoid nodules
– Prominent Brunner glands
 Lymphoid
nodules: Increased in
children
 Mononuclear inflammation
 Eosinophils
Normal Duodenal Mucosa:
Things to Remember
 Artifacts:
– Poor orientation
– Squished Brunner’s Glands
+
=
Brunner’s
Brunner’s Paste
Paste
Peptic
Duodenitis
Peptic Duodenitis
 Overexposure
to or excessive acid
 Typically confined to proximal half of
duodenum
 Variable endoscopic appearance:
– Erythema/friability
– Nodularity
– Erosion/ulcer
Peptic Duodenitis
Histopathology
Active phase
 Chronicity

– Increased mononuclear infiltrate
– Variably decreased villous height
– Variable crypt hyperplasia
– Foveolar/gastric metaplasia of epithelium
– Intramucosal Brunner gland hyperplasia
– H. pylori colonization in metaplastic epithelium
Peptic Duodenitis
Differential Diagnosis
 Drug-induced
NSAIDs)
 Crohn’s
injury (typically
disease
 Zollinger-Ellison syndrome
Take Home Point
– Minimal criteria for the diagnosis of
peptic duodenitis:

Intraepithelial neutrophils
Foveolar/gastric metaplasia

Duodenum, biopsy:

– Chronic active duodenitis.
Celiac
Disease
Definition
 Celiac
disease (CD) is an
inflammatory disease in which
certain predisposed individuals
develop a destructive inflammatory
response to certain proline-rich,
alcohol soluble proteins in grains.
Significance
– Sequelae:
Morbidity
Neoplasia
– Enteropathy-associated T-cell lymphoma
– Carcinoma
Refractory
sprue
Significance
 Diagnosis
and adherence to glutenfree diet can lead to resolution of
symptoms and decreased risk of
neoplastic complications.
Epidemiology
 Thought
to be uncommon when CD
was first described.
 Now prevalence approximately
1:100-300 in western countries.
– Less common in Latino community
– Rare in Asian populations
– Middle-east and India: similar
prevalence as west.
Pathogenesis
APC
Clinical Diagnosis

Classic symptoms
– Steatorrhea, abdominal distension, lethargy in
adults
– Abdominal distension, diarrhea, weight loss,
irritability in children

Symptomatology can be subtle and
diverse
– 4-6% of patients with iron deficiency anemia
have celiac disease
Clinical Diagnosis
http://www.aafp.org/afp/980301ap/pruessn.html
Clinical Diagnosis
 Dermatitis
Herpetiformis
– Associated with symptomatic CD in 3050% of patients.
– Also strongly associated with the
subsequent development of CD in
asymptomatic patients.
– Tx:
 Gluten
free diet
 Dapsone
Clinical Diagnosis
 Other
clinical associations
– IgA deficiency
– Diabetes mellitus
– Sjogren’s syndrome
– Autoimmune thyroiditis
– Autoimmune liver disease
– Down’s syndrome
– Lymphocytic colitis / lymphocytic
gastritis
Clinical Diagnosis

Serology
– IgA anti-tissue transglutaminase (TTG) & IgA
anti-endomysial antibodies:
 Thought
to be specific and sensitive (~ 95%)
– IgA deficient patients
– Deamidated gliadin IgG/A (DGP): Used mostly
in IgA deficient patients.

Genetic testing -- HLA DQ2 / DQ8
Clinical Diagnosis
 Endoscopic
appearances
– Scalloped folds
– Increased vascularity
– Atrophy
– Normal
Pathologic Diagnosis
Pathologic Diagnosis
Pathologic Diagnosis
Marsh Classification (Modified by Oberhuber)
Marsh
Type
IELs per 100
enterocytes
Crypt
Hyperplasia
Villous
Architecture
0
<40
Absent
Normal
1
>40
Absent
Normal
2
>40
Present
Normal
3a
>40
Present
Mild Atrophy
3b
>40
Present
Marked Atrophy
3c
>40
Present
Complete
Atrophy
Pathologic Diagnosis
– Villous atrophy / Crypt hyperplasia
Crypt
hyperplasia occurs first
Villous atrophy variable
Not specific
– Tangential sectioning
– Late change of CD
Pathologic Diagnosis
Marsh 0
Marsh 3A
Marsh 3C
Pathologic Diagnosis
– Intraepithelial
lymphocytosis
 CD8
positive Tlymphocytes
– Most specific and
sensitive histologic
feature
– Normal number of IELs
classically less than
40/100 enterocytes
Pathologic Diagnosis
Pathologic Diagnosis
– Variability of
intraepithelial
lymphocytosis
along length of
villus
– IELs over
mucosal
lymphoid
aggregates not
significant
Pathologic Diagnosis
– Increased IELs may be only
finding.
‘Latent’
celiac disease
- 5-10% of patients have CD
Patients
with dermatitis herpetiformis
1st degree relatives of CD patients
Known
CD patients on gluten-free
diet who are ingesting small amounts
of grain
Pathologic Diagnosis
Pathologic Diagnosis
Pathologic Diagnosis
Histologic Variability

From fragment to fragment
– 50% of cases
 Within
biopsy fragments
– 36% of cases
 Site
to site
– 10% showed changes in bulb only.
Weir DC, Glickman JN, Roiff T, Valim C, Leichtner AM: Variability of histopathological changes in
childhood celiac disease, Am J Gastroenterol 2010 105:207-212
Pathologic Diagnosis
Number of duodenal
biopsies
Percent positive yield
1
~ 70%
2
~ 80%
3
85 – 90%
>4
> 95%
Adults vs Children
 Marked
villous atrophy seen in 86%
of children vs 52% of adults
– Degree of villous atrophy was inversely
correlated with patient age
Vivas S, Ruiz de Morales JM, Fernandez M, Hernando M, Herrero B, Casqueiro J, Gutierrez S:
Age-related clinical, serological, and histopathological features of celiac disease, Am J
Gastroenterol 2008, 103:2360-2365
Refractory Celiac Disease
 Symptoms
despite adherence to
a gluten free diet
– Unrecognized intake of gluten
– Development of autonomous
lymphoproliferation
Refractory Celiac Disease
 Responsive
Celiac Disease: CD3+
IELs ~ CD8+ IELs
 If
CD8+ cells decrease to less than
50% of CD3+ cells:
– Poor response to steroids
– Increased risk of progression to T-cell
lymphoma
CD3
CD8
Mimics of CD
– Even in combination, villous
architecture changes and increased
IELs are not specific for CD
– The changes must be interpreted
in context of the clinical setting
Mimics of CD
 1.
 2.
 3.
 4.
 5.
 6.
 7.
Peptic duodenitis
Infections
Allergic enteritis
Crohn’s Disease
Tropical Sprue
Autoimmune Enteropathy
Immunodeficiencies
Mimics of CD
Mimics of CD
Mimics of CD
– 1. Peptic duodenitis:
Usually
increased IELs are not in the
spectrum of peptic duodenitis**
**
recent reports of increased
duodenal IELs in patients with H.
pylori gastritis
Mimics of CD
Mimics of CD
Mimics of CD
– 1. Peptic duodenitis:
One
must be especially careful when
interpreting duodenal biopsies taken
from the bulb:
– Changes of peptic duodenitis (i.e. villous
architecture changes) most severe here.
If there are increased IELs, mention celiac
disease as a possibility
Mimics of CD
– 2. Infections:
Giardia
– find organisms on biopsy
Viral enteritis (usually in children) –
can be difficult to distinguish from CD
– Clinical correlation important
Bacterial
overgrowth
Mimics of CD
Mimics of CD
Mimics of CD
– 3. Food allergies

Typically cow’s milk and eggs
– Often increased numbers of lamina
propria eosinophils are present
– Response to elimination diet
Mimics of CD
– 4. Upper GI tract Crohn’s Disease
Usually shows focal and destructive
acute inflammation with crypt abscess
formation
 Granulomas

Mimics of CD
Mimics of CD
Mimics of CD
– 5. Tropical Sprue
Can
be histologically identical to CD
Responds to antibiotics and folate
Mimics of CD
– 6. Autoimmune enteropathy
Rare disorder more common in
infants
 Associated with anti-enterocyte /
anti-goblet cell antibodies
 Usually destructive

Mimics of CD
Mimics of CD
Mimics of CD
Mimics of CD
– 7. Immunodeficiency States
Most commonly common variable
immunodeficiency (CVID)

– Absent or markedly decreased plasma
cells.
– Marked lymphoid hyperplasia
– Increased apoptotic enterocytes
Mimics of CD
Mimics of CD
Take Home Points
– 1. Especially when changes are
mild, findings are not specific for
celiac disease.
– 2. Be Careful In the Bulb!
When
there are increased IELs, celiac
disease is a distinct possibility.
Take Home Points – Find the
Mimics!
– 1. Giardiasis: Organisms.
– 2. Bacterial Overgrowth: Significant
lymphoid hyperplasia with germinal centers.
– 3. Crohn’s Disease: Focal enhanced pattern
of acute inflammation in duodenal / gastric
biopsies.
– 4. Allergy: Eosinophils in the lamina propria.
– 5. Autoimmune Enteropathy: Lack of
goblet / Paneth cells with destructive
inflammation.
– 6. Common Variable Immunodeficiency:
Lack of plasma cells.
Take Home Points
– Duodenum, biopsy:
Duodenal mucosa with complete villous
atrophy, crypt hyperplasia, and
marked intraepithelial lymphocytosis;
see note.
Note: The changes are consistent with
celiac disease in the appropriate
clinical setting.
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