Celiac Disease

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Celiac Disease

• Dr. Stephen Malnick
• Kaplan Medical Center
• Rehovot, Israel.

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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

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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

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• 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

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• Length of small intestine varies from patient to
  patient
• correlates with severity of clinical symptoms
• usually proximal small intestine more severely
  involved

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• 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, Crohns disease,
  bacterial overgrowth

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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

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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

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• 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

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Clinical features

• Mainly in whites
• rare in Africans, Japanese and Chinese
• Europe prevalence 1300 in W. Ireland, 12000 in
  other regions
• often apparent in infants
• may present at later age- reports up to 70 yr
  old!

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• 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

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• Large number asymptomatic
• 10-15 of first-degree relatives of known celiac
  patients

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GI symptoms

• diarrhea
• weight loss
• weakness
• pedal edema - protein malabsorption
• easy bruising - vitamin K malabsorption
• classic steatorrhea
• increase in stool mass in most patients

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• If ileum involved may also have diarrhea from
  bile salt malabsorption
• weight loss
• abdominal pain, nausea and vomiting are uncommon

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Extraintestinal features
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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

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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

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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

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Neurologic symptoms

• peripheral neuropathy
• myopathy
• cerebellar ataxia
• myoclonus
• cerebral atrophy and dementia
• cerebral vasculitis
• brain-stem encephalitis
• epilepsy and cerebral calcifications

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Renal and liver disease

• Glomerulonephritis
• IgA nephropathy may respond to gluten-free diet
• PBC, PSC and chronic active hepatitis
• elevated transaminases

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Autoimmune and Connective tissue disease

• Vasculitis
• cryoglobulinemia
• Sjogrens syndrome
• SLE
• selective IgA deficiency
• thyroid disease
• IDDM- and celiac both have HLA-DR3 and DQB10201
  alleles

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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

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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

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• Respond to gluten free diet
• even if villous pattern normal, number of
  gamma/delta T cells in mucosa is increased

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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

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• 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

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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

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• mucosal lesion not diagnostic
• also in hypogammaglobulinemia, tropical sprue,
  intestinal lymphoma, Zollinger-Ellinson syndrome,
  eosinophilic gastroenteritis, Crohns disease,
  bacterial overgrowth

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• 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

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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

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• Serological testing has increased diagnosis
• in UK increased diagnostic accuracy by 12
• N. Ireland- antibody (IgA AEA) prevalence of 1.2

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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

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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

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Complications

• Malignant disease
• lymphomas- intestinal and extra-intestinal
• squamous cell carcinoma of esophagus
• small intestinal adenocarcinomas
• but there may be a report bias

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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

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Complications-3

• Ulceration and stricture of small intestine
• many develop lymphoma in time

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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

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References

• Celiac Disease Diagnostic clues to Unmaskan
  ImposterMalnick, Stephen, MD. Postgraduate
  Medicine 1997 101 239-244