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Celiac Disease
• This session introduces you to the intestinal malady known
as celiac disease or celiac sprue.
• There are three reasons for looking at this disease at this
stage of your career:
• 1. You’ll learn something about an often undiagnosed
intestinal disease which can compromise the overall health
of a patient that has a pronounced morphological
component .
• 2. You’ll see the havoc the (enteric) immune system can
wreak when it receives inappropriate signals.
• 3. You’ll be able to observe the almost unbelievable
regenerative capacity of the gut (and you’ll realize you do
understand normal intestinal histology.)
Facts about Celiac Disease
• The most under diagnosed disease in the U.S.A., afflicts ~1:250, over a
million individuals.
• Underdiagnosed by ~25%.
• Patients often experience symptoms for years before being diagnosed,
average time to diagnosis is 8 years.
• Undiagnosed, untreated disease predisposes patients to osteoporosis,
anemia, chronic gastrointestinal upset, developmental and learning
disabilities in children, and certain forms of aggressive cancers
especially lymphatic cancers.
• Its proper descriptive name is “gluten sensitive enteropathy” which
indicates that it occurs as a consequence of ingesting grain products that
contain gluten, such as wheat, as explained on the next page.
•
Source:www.gluten.net
Pathogenesis:
1 A component of gluten,
gliaden, interacts with a specific
genetic form of HLA receptor
on an antigen presenting cell.
2. Tissue transglutaminase
converts glutamine residues to
glutamic acid residues making
an even more potent antigen.
3. T helper cells are activated
and, in turn, activate B and killer
T cells.
4. Plasma cell antibodies bind to
gliadin bound to enterocytes,
tissue transglutaminase and
reticular fibers surrounding gut
smooth muscle (endomysial
ab’s).
5. T cells release (inappropriate)
inflammatory cytokines as well
as inflict tissue damage.
Source:NEJM 346:180, 2002
Biopsy of the intestine in a patient with no active disease following challenge with
gluten (~ 1 week). What is particularly notable is the infiltration of the epithelium
by lymphocytes (you can see the increased number of nuclei but it’s hard to
determine specific cell types!) Enterocytes also show damage. (Source:same as slide 11)
Progress of the disease is shown on the next slide.
Normal intestinal biopsy
Small intestinal biopsy
in a patient with active
celiac disease
Source:NEJM
Normal intestinal surgical
specimen with distinct villi
Source: Pathology of the Gastrointestinal Tract, 2nd Ed.,
1998, Ed. by Ming and Goldman
Celiac disease specimen with
total loss of villi, the arrows
indicate crypt openings
Arrows indicate intraepithelial lymphocytes which, in
this disease, are destructive.
Arrowheads indicate plasma cells which are secreting ab’s against
gliaden bound to enterocytes as well against reticulin and tissue
transglutaminase resulting in tissue destruction. Source:NEJM
Biopsy from which
the previous high
power micrograph
was taken.
Villous atrophy, crypt
hyperplasia (it almost
looks like the colon)
are evident.
From what region of
the small intestine
was this biopsy taken?
Duodenum, see
Brunner’s glands?
Source:NEJM
Treatment
• There is only one treatment, strict adherence to a glutenfree diet.
• Gluten-free foods are limited, and frequently unavailable.
• Gluten-free foods cost 2-3X that of normal foods.
• Unfortunately, purchase of gluten-free products is rarely
covered by health insurance.
• The good news is that strict adherence to a gluten-free diet
can have an extraordinary outcome as seen on the next
slide.
•
Source:www.glutin.net
When the patient adheres to a strict gluten-free diet, the damaged intestinal
mucosa (often but not always ) completely regenerates including reformation
of normal villi. This is a normal biopsy; see screen 11 for a complete biopsy
Source:NEJM
series.
Sprue
Normal
As the damage recedes, the ragged, lymphocyte infiltrated-enterocytes
are replaced by normal columnar ones, thus assuring normal transport
from the lumen into the body.
Source:NEJM
This series takes you through
active disease, repair (better cell
and crypt morphology, decreased
cell infiltration) and repair
(reformation of villi and normal
crypt:villus ratio -- difficult to see)
in this micrograph.
Source: Gastrointestinal Mucosal Biopsy by Harvey Goldman; Churchill Livingston
•Study of this disease reveals
that the genes that regulate the
differentiation of the four main
cell types found in the epithelium:
1. enterocyte, 2. goblet, 3. Paneth, and
4. enteroendocrine can restore the
normal populations of these cells as
the disease recedes.
•Beyond that, the genes that regulated
villus and crypt formation
(complicated processes) during
embryonic histogenesis can be
reactivated in the adult to restore
tissue architecture.
• It’s learning how to harness these
genes to restore normal tissue
architecture that remains a major
challenge in medicine.
The Course of Celiac Disease
• The role of the physician is that of
diagnosis.
• Treatment is almost entirely dependent on
the patient.
• Cure is almost entirely dependent on the
innate ability of the body to restore normal
cell populations and tissue architecture
(recapitulating, to a great degree, embryonic
histogenesis.)