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Flashcards in 23 Celiac and Associated Diseases Deck (23):
1

Celiac disease

  • Celiac disease
  • A more descriptive, and appropriate name
  • An older term
  • Tropical sprue
  • Alternative spelling
  • Latent Celiac and gluten-sensitivity
  • If untreated,/

  • Celiac disease
    • A chronic disease characterized by an inapropriate immune reaction in the small intestine induced by gluten-containing foods
    • common, easy to daignose, and reversible
  • A more descriptive, and appropriate name, is ‘gluten-sensitive enteropathy.’
  • An older term is ‘celiac sprue,’
  • Tropical sprue, an entirely different disease caused by infection but with a similar symptoms and effect on the small intestine.
  • Alternative spelling is “coeliac disease.”
  • Latent Celiac and gluten-sensitivity
    • positive Celiac antibodies but no mucosal damage or inflammation.
  • If untreated,
    • it leads to malabsorption with associated iron and vitamin deficiencies resulting in anemia, osteoporosis, and diarrhea.
    • may increase risk of death four-fold.

2

Epidemiology

  • until the mid 1990’s it was considered/
  • Better diagnostic testing, specifically serologic testing, has revealed that it is/
  • The dramatic rise in incidence in the United States and other developed countries is thought to be due to/
  • European countries/

  • until the mid 1990’s it was considered a relatively rare disorder
  • Better diagnostic testing, specifically serologic testing, has revealed that it is one of the most common inherited diseases worldwide
  • The dramatic rise in incidence in the United States and other developed countries is thought to be due to changes in processing of food, in particular wheat products, exposing new antigens to genetically susceptible individuals.
  • European countries have both higher rates of disease and much higher antibody positivity
    • Ireland, Sweden, Finland, US
    • in Sweden, 75% of the children who were Ab positive also had abnormal small bowel biopsies.

3

The Basic Problem (p.22-23)

  • Celiac disease is a result of/
  • Pathogenesis is a multifactorial:
    • Genetic 
    • Environmental 
    • Immunologic 
    • Organ injury
    • Nutritional deficiencies

  • Celiac disease is a result of an IgA mediated immune response in genetically susceptible individuals to gluten.
  • Pathogenesis is a multifactorial:
    • Genetic – HLA DQ2 or DQ8
    • Environmental – gluten (gliadin and prolamin proteins)
    • Immunologic – IgA mediated
    • Organ injury – from chronic inflammation, primarily in the small bowel
    • Nutritional deficiencies – iron, vitamins, minerals, and later water and fats

4

Environmental (p.24-27)

  • The endosperm
  • Gluten proteins
  • In affected individuals 
    • gluten proteins/
    • an immune reaction/
    • leads to/
  • Gliadin
    •  

  • The endosperm (think white bread) part of the wheat kernel is where gluten is found where it makes up 80% of the protein.
  • Gluten proteins,
    • a combination of glutelin and prolamin
    • found in wheat, rye, and barley.
    • They are insoluable in water and poorly digested.
  • In affected individuals
    • gluten proteins traverse the small bowel mucosa
    • an immune reaction progressively damages small intestine mucosal architecture
    • leads to specific malabsorption problems early and non-specific malabsorption late in the disease.
  • Gliadin
    • the toxic alcohol-soluble fraction of gluten;
    • alpha-gliadin fraction
      • protein made of 33 amino acids
      • not digestible by gastric, pancreatic, or brush-border membrane enzymes.
    • the disease-inducing peptide remains intact in the small intestine lumen.

5

Environmental (p.24-27)

  • Exposure to gluten
    • early in life/
    • After 7 months/
  • Gluten proteins
    • traverse/
    • begin and maintain/
    • Viral or bacterial gastroenteritis/
  • factors involved.
    • In a genetically susceptible patient, exposure to specific antigens
    • A primary site of damage occurs/
    • Over years chronic inflammation causes/

  • Exposure to gluten
    • early in life (before 4 months) increases the risk of developing celiac disease.
    • After 7 months confers a lower risk.
  • Gluten proteins
    • traverse through breaks in the mucosal membrane of the small bowel and via antigen presenting cells,
    • begin and maintain the immunologic response and chronic inflammatory reaction.
    • Viral or bacterial gastroenteritis may precipitate the exposure of luminal gluten to the submucosal environment by increasing permeability.
  • factors involved.
    • In a genetically susceptible patient, exposure to specific antigens (gliadin, prolamins) triggers an inflammatory response in multiple locations.
    • A primary site of damage occurs in the mucosa and submucosa of the small intestine.
    • Over years chronic inflammation causes atrophy of the mucosa and subsequent malabsorption.

6

Genetics

  • Celiac occurs only in/
  • found in all with celiac disease
  • 90-95% of affected persons have alleles that encode/
  • Not everyone with these alleles/
  • Therefore, HLA DQ2 or DQ8/
  • HLA-DQ is part of/
    • It is these receptors that/
  • The gene that encodes for these alleles is located on/
  • haplotypes

  • Celiac occurs only in genetically susceptible individuals
  • HLA-DQ found in all with celiac disease
  • 90-95% of affected persons have alleles that encode cell surface receptors for HLA-DQ2 and the remainder (5-10%) are HLA-DQ8.
  • Not everyone with these alleles develops disease.
    • Only 10% of first-degree relatives are affected and fewer than 50% of monozygotic twins develop celiac when the other sibling is affected.
  • Therefore, HLA DQ2 or DQ8 is necessary but not sufficient to develop celiac disease.
  • HLA-DQ is part of the MHC class II antigen presenting receptor that function to distinguish self from non-self antigens.
    • It is these receptors that bind to gliadin and as a result initiate the autoimmune reaction.
  • The gene that encodes for these alleles is located on short arm of chromosome 6 and at a locus now labeled CELIAC1.
  • haplotypes
    • Usually only one of two haplotypes (from one parent) is present
    • if both are, disease is earlier and more severe.

7

Immunologic

  • Celiac disease results from/
  • Anti-gliadin:
    • Gliadin peptides/
    • These stimulate/
  • Anti-tTG and Anti-Endomysial:
    • Tissue transglutaminase/
    • Anti-endomysial antibodies are associated with/
  • The innate immune system is activated by/
  • IgA antibodies
  • Antigliadin also has an IgG antibody that can be used to/
  • these tests may be/

  • Celiac disease results from a complex interaction of inflammatory cells responding to exposure to gluten resulting in cytokines and other mediators of inflammation
    • Both the innate and adaptive immune systems come into play.
    • A number of immune mediated responses to gliadin are observed 
  • Anti-gliadin:
    • Gliadin peptides are bound to antigen presenting cells with HLA DQ2 (or DQ8) cell surface molecules.
    • These stimulate CD4+ T cells in the lamina propria to produce inflammatory cytokines, particularly interferon-gamma.
  • Anti-tTG and Anti-Endomysial:
    • Tissue transglutaminase is a small bowel enzyme that deaminates gliadin resulting in further inflammation leading to crypt hyperplasia and villous atrophy.
    • Anti-endomysial antibodies are associated with Anti-tTG and useful for diagnosis (easier to measure).
  • The innate immune system is activated by gliadin with increased interlukin-15 and activation of intraepithelial lymphocytes that damage enterocytes directly.
  • IgA antibodies
    • product of this immune response – antigliadin, anti-endomysial, antireticulin, and anti-tissue transglutaminase antibodies – which can be useful in diagnosis of celiac disease.
  • Antigliadin also has an IgG antibody that can be used to evaluate in celiac disease.
  • Since many patients with celiac are also IgA deficient, these tests may be falsely negative,
    • therefore IgA deficiency must be ruled-out at the same time antibodies are assayed.

8

Small bowel injury (p.31)

  • The chronic inflammatory process leads to/
  • Injury
    • greatest in/
    • relates to/
  • In advanced disease/
  • Clinical manifestations of celiac disease are a direct result of/

  • The chronic inflammatory process leads to mucosal damage characterized by progressive blunting of the small bowel villi.
  • Injury
    • greatest in the proximal small bowel (duodenum),
    • relates to the associated nutrient deficiencies due to malabsorption – iron (most common), fat soluble vitamins, zinc and calcium.
  • In advanced disease, carbohydrate, protein, sodium + water are malabsorbed since this occurs at all levels of the small bowel.
  • Clinical manifestations of celiac disease are a direct result of malabsorption.

9

Histologic changes (p.10-12+36)

  • Changes to the small bowel mucosal architecture
  • Small bowel histologic abnormalities in celiac disease:

  • Changes to the small bowel mucosal architecture, blunted villi, are typical but not specific to this disease.
  • Small bowel histologic abnormalities in celiac disease:
    • Villous atrophy (partial or “subtotal”)
    • Crypt hyperplasia
    • Inflammatory cell infiltration of lamina propria
    • Cuboidal enterocytes with loss of brush border and loss of basal polarity of nuclei
    • Increased numbers of intra-epithelial lymphocytes

10

Clinical Manifestations (p.20-21)

  • Clinical signs and symptoms are a result of/
    • Infants and young children present with/
    • Adolescents show/
    • Adult manifestations of celiac disease:
  • the majority of persons with celiac disease/
  • Mild and early disease results in/
  • Neurologic manifestations of advanced disease 

  • Clinical signs and symptoms are a result of malabsorption in the small intestine.
    • Infants and young children present with diarrhea, abdominal distention and failure to thrive.
    • Adolescents show short stature, neurologic symptoms and anemia.
    • Adult manifestations of celiac disease:
      • Malabsorbed nutrient --> clinical manifestation
      • Iron --> iron-deficiency anemia
      • Calcium --> osteoporosis
      • Water, electrolytes --> diarrhea
      • Protein, carbohydrates --> weight loss, bloating, diarrhea
  • the majority of persons with celiac disease are asymptomatic or subclinical and do not seek medical attention.
  • Mild and early disease results in
    • relatively non-specific symptoms such as bloating, diarrhea, constipation and weight loss
    • often misdiagnosed as irritable bowel syndrome prior to recognition of celiac disease.
  • Neurologic manifestations of advanced disease
    • Seizure, ataxia, neuropathy and myelopathy
    • It is not know if this is a result of malabsorption of micronutrients, genetic or autoimmune.

11

Usual diagnostic steps (p.40)

  • Clinical suspicion/
    • Most often this results from/
    • New diagnosis of/
  • Serology for/
    • False negative tTG can be a problem because/
    • Other antibodies/
    • A small subset of celiac patients is tTG and endomysial antibody/
      • the most sensitive means of diagnosing this disease
    • Because diagnosis confers lifelong dietary restriction most gastroenterologists/
  • Upper endoscopy with biopsy of duodenum
    • Confusing cases can be aided by/
    • requires/
    • If still not sure, some may even/

  • Clinical suspicion – diarrhea, bloating, iron deficiency, osteoporosis
    • Most often this results from non-specific GI symptoms such as weight loss, diarrhea, bloating or recognition of iron deficiency.
    • New diagnosis of osteoporosis or any other malabsorption syndrome should prompt investigation for celiac disease.
  • Serology for tTG (tissue transglutaminase) and total IgA when clinically suspicious
    • False negative tTG can be a problem because 30% of celiac patients are IgA deficient, so total IgA quantification is done in conjunction with tTG testing.
    • Other antibodies such as anti-endomysial can be helpful but are used secondarily (anti-endomysial is more expensive).
    • A small subset of celiac patients is tTG and endomysial antibody negative.
      • Therefore, endoscopic confirmation with biopsy of the duodenal mucosa remains the most sensitive means of diagnosing this disease, even in asymptomatic individuals.
    • Because diagnosis confers lifelong dietary restriction most gastroenterologists confirm diagnosis with biopsy even when tTG positive.
  • Upper endoscopy with biopsy of duodenum
    • Confusing cases can be aided by positive response to gluten-free diet as evidence by loss of inflammation and improvement in small bowel histology,
    • requires both before and after (diet restriction) endoscopy.
    • If still not sure, some may even challenge with gluten but this is rarely necessary.

12

Alternative diagnostic approaches

  • Anti-endomysial antibody testing
  • Endoscopy first
  • Gluten free diet first
  • There are many reports of resolution of GI symptoms on a gluten free diet, despite the absence of celiac antibodies or histologic changes in the duodenal mucosa. 

  • Anti-endomysial antibody testing
    • IgA antibody, more specific than tTG.
    • It is NOT as sensitive as tTG or biopsy and therefore if negative should be followed by endoscopy and biopsy.
    • This approach is reasonable and recommended
  • Endoscopy first
    • since some celiac patients are antibody negative and all eventually require endoscopy this may be the first step.
    • Since the histologic changes of celiac are not specific to this disease, antibody testing or gluten free diet challenge is always done.
    • This is an uncommon approach now that tTG and anti-endomysial testing is widely available.
  • Gluten free diet first
    • this is not recommended since it may give symptom relief in a variety of diseases and only confuses the patient (and clinician).
  • There are many reports of resolution of GI symptoms on a gluten free diet, despite the absence of celiac antibodies or histologic changes in the duodenal mucosa.
    • These are not celiac disease and may be carbohydrate maldigestion, bacterial overgrowth or irritable bowel syndrome.
    • Currently there are no protocols for routine screening of average risk, asymptomatic patients.

13

Endoscopic Findings (p.6-9)

  • Endoscopy is useful in celiac disease to obtain/
  • Non-specific abnormalities
    • correlate to/
    • These include/
    • These changes can be seen/

  • Endoscopy is useful in celiac disease to obtain tissue from the duodenum for histologic examination and to rule out other causes of weight loss and diarrhea.
  • Non-specific abnormalities
    • correlate to the microscopic changes, thus are only seen after mucosal damage has occurred.
    • These include loss or blunting of duodenal folds, mosaic pattern to the mucosa, nodularity and ‘scalloping’ of the folds.
    • These changes can be seen in any disease that causes atrophy of the duodenal mucosa.

14

Antibodies in celiac disease (p.39-41)

  • IgA endomysial Ab 
    • specificity
    • sensitivity
    • assay
  • tTG 
    • ?
    • A tTG + gliadin form when/
  • Selective IgA deficiency 
    • more common in patients with/
    • Therefore, assay for the IgA antibodies above may be/
    • Total IgA should be measured when/

  • IgA endomysial Ab
    • nearly 100% specific,
    • has a sensitivity of approximately 90%.
    • Assay is by either immunofluorescence of IgA endomysial Ab directly or ELISA for tTG (tissue transglutaminase) by enzyme-linked immunoassay, which is less expensive.
  • tTG
    • an autoantigen in celiac disease.
      • an intracellular enzyme which covalently binds glutamine to lysine.
    • A tTG + gliadin form when tTG comes in contact with gliadin.
      • This is a factor in the pathologic morphologic changes in the mucosa.
  • Selective IgA deficiency
    • more common in patients with celiac disease (1 in 40).
    • Therefore, assay for the IgA antibodies above may be incorrectly normal or absent in patients with disease.
    • Total IgA should be measured when celiac is suspected but antibodies are normal.

15

Therapy

  • A gluten-free diet/
    • Assessment and replacement of deficient nutrients/
    • This diet consists of/
    • Serum IgA anti-gliadin levels/
  • If not responding/
  • If a patient is still symptomatic despite normalization of antibody levels/
  • the presence of both IBS and celiac/

  • A gluten-free diet is the only specific therapy necessary in celiac disease.
    • Assessment and replacement of deficient nutrients should be done at diagnosis and repeated if not compliant or responding.
    • This diet consists of no intake of any foods containing wheat, barley or rye; for a life time.
    • Serum IgA anti-gliadin levels will decrease soon after therapy is begun 
  • If not responding, consider dietary errors, consultation with a skilled dietician, and repeat serology to evaluate IgA anti-gliadin levels, which correspond to disease activity.
  • If a patient is still symptomatic despite normalization of antibody levels then consider another an additional source for symptoms.
  • Celiac is relatively common and the presence of both IBS and celiac is not impossible.

16

Therapy

  • Common diet pitfalls:
  • Lack of initial response in confirmed cases/
  • Return of GI symptoms in successfully treated patients/
  • by far the most common reason for relapse of symptoms/

  • Common diet pitfalls:
    • Processed foods
    • Restaurants & take-out food
    • Visiting relatives & friends
    • Brewed alcoholic beverages
    • Medications & supplements
  • Lack of initial response in confirmed cases (antibodies + biopsy) may be classified as auto-immune enteropathy and some evolve to collagenous colitis.
  • Return of GI symptoms in successfully treated patients can also be due to lymphoma of the small bowel.
  • by far the most common reason for relapse of symptoms is dietary gluten, both intentional and non-intentional.
    • A careful and detailed investigation looking for hidden gluten – binders in medications, alcoholic beverages, protein supplements, etc. are common pitfalls.

17

Differential Diagnosis (p.48)

  • What does this duodenal biopsy suggest?
    • It could be celiac disease but/
    • Serology/
    • the clue/
  • She had Tropical sprue/
  • There are many causes of villous atrophy but celiac disease is the only one that/

  • What does this duodenal biopsy suggest?
    • It could be celiac disease but the 68 year-old woman who presented with diarrhea, anemia and weight loss did not improve with a gluten-free diet.
    • Serology was not available
    • the clue is that she is from Central America.
  • She had Tropical sprue which is due to an infection of the small intestine but because the effect on the mucosa is similar, the clinical signs and symptoms are also similar.
    • She responded to antibiotics.
  • There are many causes of villous atrophy but celiac disease is the only one that responds to the gluten-free diet and has positive specific antibodies.

18

Celiac disease and malignancy

  • Patients with celiac disease develop some form of malignancy/
  • Adenocarcinoma of the small bowel/
    • A gluten-free diet/
  • Lymphomas
    • occur/
    • most common location
  • The intensely pruritic, blistering skin lesion is associated with/
    • associated with/
    • most often occurs/
    • what results in these lesions
    • seen more often in/

  • Patients with celiac disease develop some form of malignancy at twice the rate of the average population, 50% of these being T-cell lymphomas.
  • Adenocarcinoma of the small bowel, a relatively rare condition, is much higher in celiac patients.
    • A gluten-free diet appears to protect.
  • Lymphomas
    • occur later in life, often with a relapse of symptoms despite gluten-free diet.
    • Jejunum is the most common location with a poor prognosis
  • The intensely pruritic, blistering skin lesion
    • associated with celiac sprue.
    • most often occurs on the extensor surfaces of the extremities in urticarial plaques with excoriations.
    • When gluten binds to IgA antibodies in circulation it can obstruct small vessels resulting in these lesions.
    • It is seen more often in females than males in a ration of 3:2, respectively.

19

Location of Dermatitis herpetiformis (p.50-53)

  • affected areas
  • Immunofluoresence of uninvolved skin shows/
  • homogenous linear IgA disease is seen when/
  • what resolves the cutaneous lesions

  • affected areas
    • Elbows > buttocks > knees > trunk > face
  • Immunofluoresence of uninvolved skin shows granular/speckled IgA deposits when associated with celiac disease.
  • homogenous linear IgA disease is seen when dermatitis herpetiformis is NOT associated with celiac.
  • In celiac-associated dermatitis herpetiformis, treatment of the underlying disease resolves the cutaneous lesions.

20

Non-Celiac Gluten Intolerance

  • population that believes they are gluten sensitive vs. population that has celiac disease
  • Other clinical conditions
  • treatment

  • 30% of US population believes they are gluten sensitive, only 1% of total population has Celiac Disease
  • Other clinical conditions?
    • Antibody-negative, clinical gluten “sensitivity” with normal small bowel
    • Antibody-negative, clinical gluten sensitivity with abnormal small bowel
    • Symptoms improve on gluten-free diet
    • Sensitivity to other components of wheat?
  • treatment
    • Feel better on a low-carb diet? Low FOD-MAP diet?
    • Abstain from gluten for life?

21

Other associations with Celiac

  • what caused a number of poorly understood associations to emerge
  • Microscopic colitis
  • a small percentage of patients who are antibody negative, and have intact IgA production have/
  • there are many patients with less specific GI symptoms/
  • many patients suspected or diagnosed with irritable bowel syndrome (IBS) /

  • As a result of increased awareness and testing for celiac disease and public awareness of gluten-sensitivity associated with celiac a number of poorly understood associations have emerged.
  • Microscopic colitis,
    • an idiopathic inflammation of the colon without mucosal damage
    • seen more frequently in patients with antibodies to celiac disease.
  • a small percentage of patients who are antibody negative, and have intact IgA production have the histological characteristics of celiac disease in the small bowel, clinical manifestations and respond to a gluten-free diet.
  • there are many patients with less specific GI symptoms (bloating, diarrhea, abdominal pain) that appear to improve on a gluten free diet.
  • many patients suspected or diagnosed with irritable bowel syndrome (IBS) actually have celiac disease.
    • Antibody testing is not routine for all suspected cases of IBS.

22

Making sense of testing in celiac disease (p.58)

  • MOST DIAGNOSTIC
  • SCREENING
  • if IgA DEFICIENT
  • newer, accurate
  • if IgA DEFICIENT
  • To try to rule out celiac

  • IgA endomysial antibody (IgA EMA) = MOST DIAGNOSTIC (but expensive)
  • IgA tissue transglutaminase antibody (IgA tTG)  = SCREENING
  • IgG tissue transglutaminase antibody (IgG tTG) = if IgA DEFICIENT
  • IgA deamidated gliadin peptide (IgA DGP) = newer, accurate
  • IgG deamidated gliadin peptide (IgG DGP) = if IgA DEFICIENT
  • To try to rule out celiac do HLA testing, if neg then not celiac – but 40% of the population is positive for DQ8 or DQ2 so presence of these does not rule-in celiac

23

Summary

  • Iron deficiency anemia, weight loss, diarrhea
  • Genetic predisposition – HLA-DQ2 and DQ8
  • Environmental exposure to gluten
  • Chronic inflammation in lamina propria of the small bowel - lymphocytic/plasma cells
  • Progressive small bowel mucosal atrophy
  • Malabsorption of iron, vitamins and later water and fat
  • Diagnose with celiac antibody testing, endoscopy
  • Responds to gluten-free diet