CC: Celiac Dz and Gluten Enteropathy

[liveonearth]

notes from Dr Thom's gastrogenterology notes first:

CELIAC DISEASE
inflam of SI
antigen presenting cells of lamina propria cause immune response targeting mucosa of SI
interferes with absorption of nutrients

INCIDENCE
female:male almost 3:1
1/150 in US general pop
most pts dxd in adulthood
a decade ago was uncommon, prevalence 1:1000 or lower quoted
2004 US study
general prevalence: 1/133
odds if GI sx: 1/56
odds if 1st degree relative has celiac dz: 1/22
may occur at any age but most recognized in adults in their 50's
"in childhood has become increasingly uncommon"
???why is the prevalence among children decreasing???
concordant in 60-70% of identical twins


SYMPTOMS
may be minimal or even no GI sx

IN INFANCY:
possible fulminant presentation
chronic D, abd distension
failure to thrive,
anorexia, vomiting, muscle wasting

CHILDHOOD:
median age of presentation: 4
D or constip
anemia
loss of appetite
(short stature, osteoporosis)

SYMPTOMS IN ADULT
D or constip
anemia
apthous ulcers, glossitis, stomatitis
abd pain, bloating (wt loss)
fatigue, infertility
anxiety, depression
bone pain (osteoporosis)
weakness (myopathy, neuropathy)
dermatitis herpetiformis

ASSOCIATED DISEASES
anemia
osteoporosis
type 1 diabetes
AI thyroid disease (Hashimotos, Graves)
mb assoc w/ other AI dz: PBC, Sjogren's etc

DDX
anorexia nervosa
autoimmune enteropathy
bacterial overgrowth
collagenous sprue ??
Crohn's dz
HIV
hypogammaglobulinemia
infective gastroenteritis, ischemic enteritis
intestinal lymphoma
IBS
lactose intolerance, soy protein intolerance
pancreatic insufficiency
tropical sprue ??
TB
Whipple's dz ??
Zollinger-Ellison syndrome

DIAGNOSIS
was hard to do before there was testing for endomysial antibodies
screen using anti- endomysial or TTG ABs
anemia (micro hypo or normo normo with incr RDW)
incr AST
low albumin
low or "too good" cholesterol ??? relative to diet and presentation I guess
incr alk phos
BX to confirm DX: may find villous atrophy
ELISA test for endomysial and anti-tissue transglutaminase antibodies
(ELISA = enzyme linked immunosorbent assay system)
specificity of anti-endomysial indirect IF approaches 100%
sensitivity of anti-gliadin and anti-TTG ELISA approaches 100%

TREATMENT
permanent withdrawal of gluten from the diet
there is no alternative to this tx
monitor progress

GLIADIN EFFECT DOSE DEPENDENT
effect of gliadin on intestine is dose dependent
at 500mg there is increased permeability of the gut
at 50-100mg there are minimal changes on biopsy
at 10mg there's no change
10mg gliadin ~ 250mg wheat flour ~ less than 1/8 a teaspoon of flour

NUTRITION
(these nutrients are poorly absorbed in celiac pts)
iron
folic
calcium
fat soluble vits

PROGNOSIS
with adherence to gluten free diet, 100% remission
most pts show rapid clinical response: sx better in weeks, histol of bowel slower
complete mucosal recovery in months-years

COMPLICATIONS
osteoporosis (all pts with bone loss should be screened for celiac, use endomysial or TTG ABs
malignancy: enteropathy associated T-cell lymphoma
also CA of SI, esoph, pharynx

PATHOGENESIS
T-cell mediated immune response in genetically predisposed people
95% express HLA-DQ2 heterodimer allels DQA1*0501 and DQB1*-2-1
(20-30% of normals carry these alleles)
5% HLA-DQ8 heterodimer allels DQA1*0301 and DQB1*0302
these allels present gluten-derived gliadin peptides to stimulate T cells
**delaying exposure to gluten may alter disease
viral exposures may trigger immune response
adenovirus type 12 implicated
T cells may react with tissue transglutaminase
(TTG is main part of endomysium autoantigen)

GLUTEN SOURCES
wheat: bran, starch, kamut, spelt, triticale
barley: malt, extract, flavoring
rye
oats: syrup, bran, cereal
(exclusion of oats questionable, some pts tolerate, oats can get gluten on them in processing)
bulgur
couscous
cereal binding
seminola
graham flour

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ON T CELLS IN CELIAC DZ
from Gut. 2003 February; 52(2): 162. PMCID: PMC1774969
Gliadin peptide specific intestinal T cells in coeliac disease
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1774969
K E A Lundin and L M Sollid (immunology researchers in Oslo, Norway)
coelica dz associated with HLA-DQ2 (majority of pts, the rest have HLA-DQ8)
HLA, human leucocyte antigen, type I is on all cells, type II is on APC's
theory is that HLA-DQ2&8 predispose to coeliac dz
by presenting peptides to T cells in intestinal mucosa
if T cells recognize the antigen presented, an inflammatory response might cause dz
evidence is adding up to support this theory more and more
small intestine lesion shows inflam, T cells infilt of lamina propria, epithelium
(lamina propria = a loose CT layer under the epithelium of a mucosal lining
contains capillaries, lymph tissue, and a lacteal draining from intestine to hep portal)
significance of T cells in epithelium not known
Ts unlikely to recognize gluten presented by HLA-DQ2
researchers suspect T's in lamina propria are "key players"
also in lamina propria: CD4+ T cells and dendritic cells (both APCs w/HLA-DQ2)
gluten reactive T cells first isolated some 10 years ago from SI mucosa
several gliadin epitopes are known
T-cell recognition depends on action of SI enzyme tTG, tissue transglutaminase
tTG converts glutamine residues (in gluten)-->glutamic acid
new study n=4 adults
small intestinal biopsies were challenged ex vivo with gluten
then cell suspension made, T cells cultured until there were enough to test
this part of the process didn't go easily
found both polyclonal and monoclonal T cell lines
found most T cells reactive a known α-gliadin that causes rxns
no new epitopes were found
there are multiple gluten T cell epitopes in coeliac disease
the T cell receptor usage by gluten specific T cells is diverse
possible treatments:
1) inhibit T-cell activation by blocking HLA-DQ2 binding to the peptide
2) inhibit tissue transglutaminase to prevent gluten deamidation
3) supplement peroral peptidase to complete digestion of immunostimulatory peptides
(peroral peptidase is a normal brush border enzyme that would be deficient w/ enteropathic dz)
on peptidases of brush border: http://www.ncbi.nlm.nih.gov/pubmed/2869093
so far no treatments available except gluten free diet

alpha-1 gliadin shown in yellow:


TISSUE TRANSGLUTAMINASE (from Wikipedia)
Tissue transglutaminase (abbreviated as TG2 or tTG) is an enzyme (EC 2.3.2.13) of the transglutaminase family. Like other transglutaminases, it crosslinks proteins between an ε-amino group of a lysine residue and a γ-carboxamide group of glutamine residue, creating an inter- or intramolecular bond that is highly resistant to proteolysis (protein degradation). It is particularly notable for being the autoantigen in coeliac disease, but is also known to play a role in apoptosis, cellular differentiation and matrix stabilisation.[1]

HSPs and GLIADIN PROMOTE DEVELOPMENT OF PEPTIDASE ABs IN AUTISTIC KIDS AND ADULTS WITH AI DZ
Heat Shock Protein and Gliadin Peptide Promote Development of Peptidase Antibodies in Children with Autism and Patients with Autoimmune Disease
http://cvi.asm.org/cgi/content/abstract/11/3/515
Clinical and Diagnostic Laboratory Immunology, May 2004, p. 515-524, Vol. 11, No. 3
E-mail: immunsci@ix.netcom.com
researchers in CA looking for a mechanism for AI in autism
postulated that gliadin peptides, heat shock protein 60 (HSP-60), and streptokinase (SK)
bind peptidases-->autoantibody production against these components
GET THAT? AUTOIMMUNE RXN TO ONE'S OWN PROTEIN DIGESTING ENZYMES
assessed this idea with autistic and mixed CT dz pts
assoc w/ antigliadin and anti-HSP antibodies, these pts developed autoABs:
1) anti-dipeptidylpeptidase I (DPP I)
2) anti-dipeptidylpeptidase IV (DPP IV [or CD26])
3) anti-aminopeptidase N (CD13) autoantibodies
significant percentage of pts had high IgG, M, or A against 3 peptidases, gliadin & HSP-60
AB's are specific for one thing, tested by introducing antigen to see what bound
theory: (i) superantigens (e.g., SK and HSP-60) and dietary proteins (e.g., gliadin peptides) in individuals with predisposing HLA molecules bind to aminopeptidases and (ii) they induce autoantibodies to peptides and tissue antigens.