Causative Antigen

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  • Celiac disease (CD) caused by immunologic non-IgE- mediated reaction to gliadin component of dietary glutens found in wheat, barley, and rye.
  • Controversial whether oats also cause disease (lack of oat tolerance in CD may be due to contamination of oat grains with other grains)
    • The majority of patients with CD can consume a moderate amount of pure oats (up to 70 g per day in adults and 25 g per day in children) without side effects


Clinical Features

Disease Patterns

Features
Classic
  • Symptoms of malabsorption (steatorrhea, weight loss, or other signs of nutrient or vitamin deficiency)
  • Presence of characteristic histologic small intestinal biopsy changes (including villous atrophy)
  • Resolution of the mucosal lesions and symptoms with elimination of gluten-containing foods, usually within a few weeks to months.
Atypical
  • Extraintestinal symptoms predominant, with few/no GI symptoms noted by patient
  • Diagnosis requires serologic testing, biopsy evidence of villous atrophy, and improvement of symptoms on a gluten-free diet.
Subclinical/silent-----------
  • No clinical symptoms, but have a positive serologic tests and biopsy evidence of villous atrophy (usually detected by screening of high-risk groups)
  • After treatment with a gluten-free diet, many of these patients retrospectively recognize symptoms that they had not previously considered to be abnormal.
Potential
  • Patients with negative intestinal biopsies but have characteristic immunologic abnormalities (positive serology or increased intraepithelial lymphocytes).
  • These patients often have a genetic predisposition, especially HLA-DQ2, and a first-degree relative with CD.
Latent
  • 2 variants have been identified:
    • Latent CD after disese resolves or is outgrown: disease present in past (usually in childhood), resolved completely with a gluten-free diet, and disease did not recur when a normal gluten-containing diet is resumed later in life.
    • Latent CD before disease develops: normal mucosa was found at an earlier occasion while on a gluten-containing diet, but CD developed later in life.
Refractory
  • Patients with true disease (ie, not a misdiagnosis) who do not or no longer respond to a gluten-free diet.
  • Some of these patients develop complications such as ulcerative jejunoileitis or enteropathy-associated T-cell lymphoma.
Gluten sensitivity
(controversial)
  • Clinical response to a gluten-free diet in the absence of serologic/histologic findings

  • Epidemiology
    • Biphasic incidence: 6-24 months old with first introduction of gluten into diet then 10-40 years old.
    • Prevalence increases with age and up to 15% of newly diagnosed are >65 years old
    • Occurs primarily in whites of Northern European ancestry (rare in Chinese, Japanese, subsaharan African)
    • High risk groups:
      • 99% with CD have HLA DQ2 and/or DQ8 (vs. 40% of the general population) thus CD is highly unlikely in patients without these haplotypes
      • Down syndrome
      • 1st and 2nd degree relatives of patients with celiac disease
      • Type 1 diabetes mellitus
      • IgA deficiency
      • Turner syndrome
      • Williams syndrome
      • Autoimmune thyroiditis
  • Signs/symptoms:
    • GI:
      • Young child: chronic diarrhea, anorexia, abdominal distension/pain, weight loss, failure to thrive, malnutrition; some have vomiting
      • Older child/adult: as above, constipation or diarrhea (bulky, foul-smelling), stools may float due to steatorrhea, flatulence, distension
      • Secondary lactose intolerance
      • "Celiac crisis" - rare life-threatening syndrome, mostly in children, characterized by severe diarrhea, hypoproteinemia, metabolic/electrolyte imbalances
    • Skin:
      • Dermatitis herpetiformis (DH)
        • Up to 24% of adults with celiac have DH, 85% with DH have intestinal biopsy changes
        • Pruritic and burning papular vesicular eruption usually located symmetrically on the extensor surfaces of the elbows, knees, buttocks, sacrum, face, neck, trunk, and occasionally within the mouth
      • Apthous stomatitis
      • Chronic urticaria - case reports of urticaria in children and adults with CD that resolve on gluten-free diet
      • Other associated skin findings: acquired icthyosis, cutaneous amyloid, cutaneous vasculitis, eczema, epidermal necrolysis, nodular prurigo, pityriasis rubra pilara, pustular dermatitis
    • Autoimmune disease - associated with development of type 1 DM, autoimmune thyroid disease, connective tissue disease
    • Growth and development:
      • Failure to thrive
      • Short stature
      • Delayed puberty
    • Neuropsychiatric disease - neurologic or behavioral symptoms may be primary/initial symptom
      • Hypotonia
      • Cerebellar ataxia
      • Developmental delay, learning disorders and ADHD
      • Headache
      • Mood changes, depression, anxiety
      • Carpal tunnel
      • Epilepsy with occipital calcifications
      • Myopathy
    • Dental enamel defects
    • Metabolic bone disease - osteomalacia/osteoporosis due to vitamin D and calcium malabsorption
    • Arthritis
    • Liver disease - mild elevation of AST, ALT (with case reports of severe liver disease)
    • Iron deficiency (with or without) anemia - not responsive to iron replacement
    • Hyposplenism - etiology unknown
    • Kidney disease - glomerular IgA deposition in up to a third, most without adverse consequences
    • Idiopathic pulmonary hemosiderosis
      • Lane-Hamilton syndrome - coexistence of CD with pulmonary hemosiderosis, both improving with gluten-free diet
    • Reproductive/Gynecologic
      • Females with increased frequency of later menarche, earlier menopause, secondary amenorrhea, recurrent miscarriage, and infertility
      • Males with abnormal sperm, androgen resistance
    • Myocarditis, cardiomyopathy
    • Atrophic glossitis
    • Pancreatitis
    • Malignancy - increased risk of lymphomas and GI cancers in adults
    • Mortality - increased vs. general population likely due to malignancy, possibly decreased with adherence to gluten-free diet

Note:
  • CD presents as a clinical spectrum from subclinical/silent to classical disease
  • In children with subtle symptoms and CD detected by screening, the most common symptoms included: Iron deficiency with/without anemia, recurrent abdominal pain, mood changes, recurrent aphthous stomatitis, poor appetite, recurrent diarrhea, short stature, abdominal distention, constipation, pubertal delay, hypoalbuminemia



Diagnosis

Indications for Testing

  • Individuals without other explanations for signs/symptoms above
  • Chronic GI symptoms including diarrhea, malabsorption, failure to thrive, constipation, abdominal pain, distension, or vomiting (includes patients with symptoms suggestive for IBS or lactose intolerance which frequently coexist with CD)
  • All members of high-risk groups (particularly if symptomatic): 1st degree relatives of patients with CD, autoimmune thyroiditis, type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency.
    • Controversial to test asymptomatic children in high risk groups. If screening done, perform when patient at least 3 years old and on a gluten-containing diet for at least 1 year. If initial results are negative, screening tests should be repeated at regular intervals (eg. 3-5 years), or when symptoms develop.


Lab Testing

Useful Tests
Serum IgA level
  • IgA deficiency found in 2% with CD
  • Deficiency may result in false negative celiac disease IgA antibody testing
Anti-tTG (tissue transglutaminase) IgA
  • Recommended as first-level screening test
  • Best cost-effective single test with good sensitivity/specificity
  • May be false positive in setting of other autoimmune diseases, including type 1 diabetes
  • Sensitivity/specificity >95%
Anti-tTG IgG
  • Obtain instead of Anti-tTG IgA in patient with IgA deficiency
  • Widely variable sensitivity (12.6-99.3%) and specificity (86.3-100%)
Anti-endomysial antibody (EMA) IgA
  • Expensive, time consuming, and accuracy varies by lab expertise but may be useful in patients with uncertain diagnosis
  • Should only be used as a confirmatory test in the case of equivocal or possibly false positive anti-tTG
  • Sensitivity >90% and specificity >98%
  • False negative in IgA deficiency
DGP (Deamidated Gliadin Peptide) IgG
  • Second generation antigliadin antibody test that yields diagnostic accuracy similar to tTG IgA
  • Sensitivity/specificity >90%
HLA typing for DQ2 and DQ8
  • May be useful in individuals with equivocal intestinal biopsy findings since CD is very unlikely if neither HLA type is present
Less Useful Tests
Antigliadin IgA
  • Sensitivity >52%, specificity >72%
  • False negative in IgA deficiency
Antigliadin IgG
  • Sensitivity >83%, specificity >47%
Antireticulin IgA
  • Found in 60% of CD and 25% of DH but not in other autoimmune diseases
  • Anti-reticulin IgG found in other diseases (bullous dermatoses) and sometimes normal patients
  • No longer commonly used
Note:
  • Combination of anti-tTG and DGP antibody levels may be best combination of tests for serologic diagnosis of CD
  • All testing should be performed on a gluten-rich diet (at least 1-3 months before test obtained)
    • Antibody levels remain elevated for 1-12 months after gluten removed from diet therefore it may be reasonable to obtain serology in patients who have only recently begun a gluten-free diet.
  • Serologic testing may not be as accurate in children <5 years and is less accurate <2 years old


Biopsy

  • Note that European guidelines (2012) suggest that a biopsy of the small intestine may not be required in children with typical symptoms, a high titer of antiā€“tTG antibodies (>10 times the upper limit of normal), and predisposing HLA genotypes

Small Intestine
  • Patients with positive serologic testing should have an intestinal biopsy to establish the diagnosis
  • Biopsy should be performed while on a gluten-containing diet.
  • Multiple biopsies should be taken from the distal duodenum and duodenal bulb and interpreted by an expert pathologist; the disease may have a patchy distribution.
  • Histologic findings in CD range from increased intraepithelial lymphocytes to a flat mucosa with total mucosal atrophy, complete loss of villi, enhanced epithelial apoptosis, and crypt hyperplasia
  • Severity of abnormality does not necessarily correlate with clinical symptoms
  • If serology positive but biopsy negative, consider repeating biopsy after 6-12 weeks on high gluten diet
Skin (Dermatitis Herpetiformis)
  • DH diagnosis confirmed by the demonstration of granular IgA deposition in an area of the skin not affected by blistering, along the subepidermal membrane.
  • Biopsy alone is sufficient to make the diagnosis of DH. Anti-tTG antibodies are elevated in patients with DH.
  • Many experts recommend treatment based on the results of the skin biopsy alone, and an intestinal biopsy is not required.


Algorithm

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Fasano (2012)

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Treatment

Indications for Treatment
Treat
  • Positive intestinal biopsy and CD symptoms (including nonspecific symptoms such as constipation or abdominal pain).
  • Positive intestinal biopsy and belonging to high-risk group (eg, relatives of patients with established celiac disease, or patients with type 1 diabetes), whether or not there are associated clinical symptoms.
  • Dermatitis herpetiformis confirmed by skin biopsy.
Don't treat
  • Negative intestinal biopsy (ideally expert review of multiple biopsies), positive serology, no symptoms
  • Monitor clinically and biopsy if symptoms develop
Maybe treat (controversial)
  • Negative intestinal biopsy, positive serology, with symptoms of CD - most with this profile might eventually develop intestinal biopsy changes
  • Life-long gluten-free diet
    • Strict elimination of wheat, rye, barley.
    • Oat elimination controversial - consider limiting to 50-60 g/day in mild disease and strict elimination in severe disease
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  • "CELIAC"
    • Consultation with dietitian
    • Education
    • Lifelong gluten-free diet
    • Identification and treatment of nutritional deficiencies: iron, calcium, phosphorus, folate, B12, and fat-soluble vitamins.
    • Access to an advocacy group
    • Continuous long-term follow-up by a multidisciplinary team
  • Secondary lactose intolerance - avoidance of lactose until small intestine normalizes with gluten-free diet
  • Dermatitis herpetiformis - gluten free diet results in improvement in 6-12 months therefore dapsone usually started (improves skin but not intestinal disease)
  • Hyposplenism - pneumoccocal vaccination
  • Bone health - consider DEXA scan in adults, treatment of osteoporosis
  • Consider screening 1st degree family members for CD (particularly siblings)


Monitoring

  • 70% with clinical improvement 2 weeks after starting diet
  • Obtain pre-diet tTG IgA (or IgA antigliadin) level and monitor decline over time - should fall to baseline level 3-12 months later depending on pre-treatment level (eg check level pre-diet and at 6 months). If patient remains well, check level annually to monitor adherence and also obtain level if symptoms recur.
    • tTG IgA half-life is 6-8 weeks
    • If the levels do not fall, the patient is usually continuing to ingest gluten intentionally or inadvertently
    • Use same laboratory for testing. Minor fluctuations in IgA antigliadin or IgA tTG levels are the norm and should not be overinterpreted.
    • IgG antigliadin level also falls after diet but is slower to fall than antigliadin IgA
  • Repeat Biopsy
    • Normal serology does not reliably indicate recovery from villous atrophy
    • Biopsy not indicated for patients with the following profile: initially presented with CD symptoms, positive antibodies, and positive intestinal biopsy (villous atrophy) followed by resolution of symptoms and marked decrease in antibodies on a gluten-free diet.
    • For other cases, consider repeat biopsy 9-12 months after starting gluten free diet
  • Gluten rechallenge (4 slices of bread for 4-6 weeks) - generally not required unless diagnosis remains in question. A rare complication of challenge is "gliadin shock" with fulminant diarrhea requiring treatment with steroids.




References