Celiac Disease

Dr. Stephen Malnick

Kaplan Medical Center
Rehovot, Israel.
 Celiac Disease
 Malabsorption of nutrients by damaged
portion of small intestine
 characteristic but not specific lesion of
small intestinal mucosa
 prompt clinical improvement after
withdrawal of cereal grains
 Pathology
 Loss of normal villous structure
 infiltration of plasma cells and lymphocytes
into the lamina propria
 increase in the number of intraepithelial
lymphocytes and gamma/delta T cells
 These changes decrease the amount of
epithelial surface available for digestion and
absorption in the involved bowel
 many mucosal enzymes are altered due to
the damage to the absorptive cells
 decrease in disaccharidases, peptidases,
alkaline phosphatase, ATPase, and esterases
 Length of small intestine varies from patient
to patient
 correlates with severity of clinical
symptoms
 usually proximal small intestine more
severely involved
 Treatment with a gluten-free diet results in
improvement in the intestinal structure
 BUT mucosal lesion not diagnostic
 also in hypogammaglobulinemia, tropical
sprue, intestinal lymphoma, Zollinger-
Ellinson syndrome, eosinophilic
gastroenteritis, Crohn’s disease, bacterial
overgrowth
 Pathogenesis
 Wheat and other grains contain a water--
insoluble protein component termed gluten
 alcohol extraction of gluten results in
gliadin
 gliadin is toxic when inserted into the small
intestine
 Mechanism of injury
 Immune response to gluten?
 Production of anti-gliadin antibody linked
to presence of CD8+ T cells in lamina
propria
 genetic factors-increased incidence of HLA-
B8 and HLA-DR3 and also HLADQ2 and 8
 homology of 12 AA sequence in type 12
adenovirus E1b protein and anti-gliadin
 Recently shown that single peptide from
alpha-gliadin may be dominant epitope
 one peptide shown to have most ability to
stimulate intestinal T cells and also
circulating CD4 cells
 Clinical features
 Mainly in whites
 rare in Africans, Japanese and Chinese
 Europe prevalence 1:300 in W. Ireland,
1:2000 in other regions
 often apparent in infants
 may present at later age- reports up to 70 yr
old!
 Most symptoms related to malabsorption
 extensive lesion in proximal duodenum to
distal ileum produces severe malabsorption
 limited involvement may not have severe
symptoms
 only iron or folate deficiency
 Large number asymptomatic
 10-15% of first-degree relatives of known
celiac patients
 GI symptoms
 diarrhea
 weight loss
 weakness
 pedal edema - protein malabsorption
 easy bruising - vitamin K malabsorption
 classic steatorrhea
 increase in stool mass in most patients
 If ileum involved may also have diarrhea
from bile salt malabsorption
 weight loss
 abdominal pain, nausea and vomiting are
uncommon
Extraintestinal features
 Hematopoietic
 anemia - iron or folate deficiency, but also
increased blood loss
 B12 deficiency in severe cases
 hyposplenism - may resolve with dietary
therapy
 thrombocytosis with Howell-Jolly bodies
 bleeding diathesis
 Osteopenic bone disease
 decrease Ca absorption
 decrease in absorption fat-soluble vitamin D
 binding of Ca and Mg in lumen by
unabsorbed dietary fatty acids
 Osteopenic bone disease
 Osteoporosis with bone pain and pathologic
fractures
 paresthesia, muscle cramps and tetany if
severe hypocalcemia
 chronic can result in secondary and even
tertiary hyperparthyroidism
 problems with premenopausal bone mass
 Neurologic symptoms
 peripheral neuropathy
 myopathy
 cerebellar ataxia
 myoclonus
 cerebral atrophy and dementia
 cerebral vasculitis
 brain-stem encephalitis
 epilepsy and cerebral calcifications
 Renal and liver disease
 Glomerulonephritis
 IgA nephropathy may respond to gluten-free
diet
 PBC, PSC and chronic active hepatitis
 elevated transaminases
 Autoimmune and
Connective tissue disease
 Vasculitis
 cryoglobulinemia
 Sjogren’s syndrome
 SLE
 selective IgA deficiency
 thyroid disease
 IDDM- and celiac both have HLA-DR3 and
DQB1*0201 alleles
 OB-GYN
 Impaired fertility in women
 high incidence of spontaneous abortion
 low birth-weight babies
 reduced breast milk production
 paripartum exacerbation or first
presentation
 correctable with gluten-free diet
 Dermatitis herpetiformis
 Papulovesicular skin disease
 IgA deposits in the basement membrane
 60% of DH patients have moderate to
severe villous atrophy
 DH patients with normal small-bowel
mucosa respond to gluten with a mucosal
lesion
 common HLA linkage
 Respond to gluten free diet
 even if villous pattern normal, number of
gamma/delta T cells in mucosa is increased
 Diagnosis
 Be aware of variable spectrum and subtle
presentations
 Lab tests - malabsorption
 decreased iron, folate, and rarely low B12
 low serum albumin
 increased PT
 D-xylose test confirms malabsorption but
not diagnostic
 Small bowel films may show
 dilatation of small intestine, coarsening of
mucosal folds
 fragmentation and flocculation of barium
within gut lumen
 delineates the extent of the disease and
checks for other pathology
 Peroral biopsy
 Introduced in 1950s as capsules
 now obtained at GI endoscopy
 endoscopic picture of gross absence of
duodenal folds and scalloping
 normal biopsy effectively excludes celiac
 but DD for classic lesion
 mucosal lesion not diagnostic
 also in hypogammaglobulinemia, tropical
sprue, intestinal lymphoma, Zollinger-
Ellinson syndrome, eosinophilic
gastroenteritis, Crohn’s disease, bacterial
overgrowth
 Diagnosis made by clinical response to
gluten-free diet and an improvement in the
mucosal histology
 may require months or years of Rx
 ESPGN protocol requires third biopsy after
rechallenge with gluten
 Serological diagnosis
 Anti-gliadin antibodies IgG and IgA
 45% positive predicitive value and 97%
negative predicitive value
 anti-endomysial antibody- directed against
membrane of primate smooth muscle
bundles
 sensitivity of 100% and specificity of 99%
 IgA test is easier to use than IgG
 Serological testing has increased diagnosis
 in UK increased diagnostic accuracy by
12%
 N. Ireland- antibody (IgA AEA) prevalence
of 1.2%
 Tissue transglutaminase (tTG)
 Major autoantigen of celiac disease
 ELISA tests based on tTG
 guinea pig and also human ELISA
 interestingly tTG can deamidate glutamine-
rich proteins such as gliadin
 Response to diet
 If no response within a few weeks then
reconsider diagnosis
 check for incomplete removal of gluten
from the diet
 less severely damaged distal mucosa
recovers more rapidly than maximally
damaged proximal mucosa
 Complications
 Malignant disease
lymphomas- intestinal and extra-intestinal
squamous cell carcinoma of esophagus
small intestinal adenocarcinomas
but there may be a report bias
 Complications -2
 Refractory sprue
 respond early on to gluten withdrawal but
after a period of time relapse despite dietary
adherence
 few respond to steroids
 endomysial antibody negative
 Complications-3
 Ulceration and stricture of small intestine
 many develop lymphoma in time
 For the future
 Use defined peptide to re-induce
immunological tolerance
 engineer peptides that lack residues
necessary for stimulating T cells but still
compete for binding to pathogenetic HLA-
DQ molecules
 genetically engineer wheat plants so that
critical peptides removed or mutated
 References
Celiac Disease: Diagnostic clues to Unmaskan Imposter 
Malnick, Stephen, MD. Postgraduate Medicine 1997; 101: 239-244