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GLUTEN FREE, POSITIVE TTG: NOW WHAT?Jennifer Jin MD FRCPCRoyal Alexandra Hospital

GI for GPs 23 April 2016

Objectives

• Describe the role of “biopsy-free” diagnosis of celiac disease (CD)

• Describe the impact of a gluten free diet (GFD) on diagnostic tests for CD

• Discuss the role of tissue transglutaminase (tTG) monitoring in a patient with CD

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Disclosures

• None

Gluten Free Museum

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Celiac Disease

• Immune mediated reaction triggered by gliadin in gluten in genetically predisposed individuals, which causes injury to the small bowel with loss of absorptive surface area and decreased digestive enzymes

Green et al. Celiac Disease. N Engl J Med 2007; 357:1731-1743

Fasano, A. Scientific American 2009; 301, 54 - 61

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Prevalence of CD

• Prevalence is about 1%

• Prevalence varies in different parts of the world• 2% in Finland

• Probably similar prevalence many parts of the world

• Middle East, South Asia, South America, and North Africa

• Exceptions are sub-Saharan Africa, China, and Japan

• Higher risk in first degree relatives – 10%• Even higher risk in siblings, up to 20%

• Type 1 diabetics 3-10%

Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013; 108:656

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Dermatitis Herpetiformis

Medscape

CD associations

• Thyroiditis

• Type 1 diabetes

• Autoimmune myocarditis, Idiopathic dilated cardiomyopathy

• Sjögren's syndrome

• Systemic lupus erythematosus

• Autoimmune hepatitis, Autoimmune cholangitis, Primary biliary cirrhosis

• Inflammatory bowel disease

• Systemic and cutaneous vasculitis

• Trisomy 21, Turner’s syndrome, William’s syndrome

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Why go gluten free?

• Resolution of GI symptoms

• Decrease risk of malignancies and mortality • Small bowel adenocarcinoma

• Esophageal cancer

• B-cell and T-cell non-Hodgkin lymphomas (including intestinal T-cell lymphomas)

• Improvement of bone mineral density

• Deceases risk of infertility, spontaneous abortions, pre-term deliveries, and low birth weight infants

Testing for CD

• Autoantibodies:• IgA endomysial antibodies (anti-EMA IgA) – sensitivity 85 – 98%;

specificity 97 – 100%

• IgA tissue transglutaminase antibodies (anti-TTG IgA)–sensitivity 90 – 98%; specificity 95 – 97%

• Antibodies targeting the offending agent (gliadin):• Conventional antigliadin antibodies (AGAs – no longer done)

• Antibodies against synthetic deamidated gliadin peptides (DGPs):

• Anti-DGP IgA– sensitivity 94%; specificity 99%

• Anti-DPG IgG– sensitivity 92%; specificity 100%

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tTG IgA

• Selective IgA deficiency is more common in patients with celiac disease than in the general population

• 2 – 5% versus 0.5%

• Test for IgA levels concurrently with anti-tTG to avoid a false negative

• False positive of anti-tTG IgA is rare

Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol 2013; 108:656.

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Gluten Free Museum

Role of biopsy in CD

• 2012 European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) guidelines:

• Histological assessment may be omitted in symptomatic patients who have high IgA anti-TG2 levels (10 times above ULN), verified by EMA positivity, and are HLADQ2 and/or HLA-DQ8 heterodimer positive

Husby S et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol.Nut 2012. 54(1), 136–160

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Husby S et al. European Society for Pediatric Gastroenterology, Hepatology, and Nutrition guidelines for the diagnosis of coeliac disease. J. Pediatr. Gastroenterol.Nut 2012. 54(1), 136–160

Role of biopsy

• Study of 324 symptomatic and asymptomatic patients with celiac disease (97 children and 227 adults) using a cutoff for anti-tTGof 30U to predict Marsh 3 atrophy found that 65% of duodenal biopsies could be avoided

• But, considering children and adults separately, 95% of children, but only 53% adults with true atrophy, would have avoided biopsy

Vivas S, Ruiz De Morales JG, Riestra S et al. Duodenal biopsy may be avoided when high transglutaminase antibody titers are present. World J. Gastroenterol. 2009; 15(38), 4775–4780

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Positive data in adults

BurginWolff A, Mauro B, Faruk H. Intestinal biopsy is not always required to diagnose celiac disease: a retrospective analysis of combined antibody tests. BMCGastroenterol. 2013; 13, 19.

Role of biopsy• In asymptomatic patients with low positive titer antibodies,

biopsy is almost always required to confirm or exclude CD, due to the risk of false positive serology

• Effect of pre-test probability• Biopsy reveals grade of mucosal abnormality which is

helpful if follow-up biopsies are needed, especially in patients with persistent or recurrent symptoms

• Important to confirm a correct diagnosis as a lifelong GFD is expensive and socially inconvenient• Definitive diagnosis may help compliance

• Important in regards to follow up for other CD related considerations, screening family members, and monitoring for complications

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Testing and GFD

• Ideally testing should be done on a gluten-containing diet

• If the duration of GFD has been brief (<1 month), serology and histology are often still abnormal

• However, some patients will also quickly revert to normal on a GFD

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Testing on a GFD

• Check serology on a GFD

• If negative can consider HLA testing or gluten challenge

HLA haplotype

• 95% of patients carry an DQ2 haplotype while the remaining 5% carry DQ8

• If negative then CD is very unlikely

• NPV>99%

• HLA testing also helpful biopsy results are equivocal

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Gluten challenge

• Formal: 3g per day of gluten (2 slices of bread) for 2 weeks and if tolerated, extend for 6 more weeks with biopsy and repeat serology at 8 weeks

When does serology normalize

• After 6 – 12 months on a GFD, 80% will be negative

• By 5 years, >90% will have negative serology

• Lower titre less sensitive for ongoing mucosal abnormality

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Symptom improvement on GFD

• Up to 70% of patients have improved symptoms after 2 weeks of a GFD

How much gluten is “safe”?

• 10mg per day probably will not cause mucosal injury in most patients

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Oats

• Commercial oats are likely contaminated with gluten

• Pure oats may be safe in limited quantities

• Limit to 50-60g per day

• Reintroduce only in mild disease or after a GFD is maintained

• Better to avoid in severe CD

Oats

• Subset of CD patients may be intolerant to pure oats avenins

• About 5%

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Untreated CD – micronutrient deficiencies

• Iron

• Folic Acid

• Vitamin B12 and B6

• Vitamin D

• Copper, zinc, carnitine

Monitoring of CD

• TTG IgA

• BMD

• Pneumococcal vaccination • Hyposplenism

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Gluten Free Museum

Non-responsive or refractory CD• Persistent symptoms, signs or lab abnormalities typical of

CD despite 6 – 12 months of GFD• 7 – 30% of patients

• Most common cause is inadvertent gluten ingestion (35-50%)

• Other causes:• Irritable bowel syndrome (normal mucosa)• Other dietary intolerances such as lactose intolerance (normal

mucosa)• Pancreatic inefficiency (normal mucosa)• Microscopic colitis • Small bowel bacterial overgrowth (may have villous atrophy)• True refractory CD, ulcerative jejunitis, lymphoma

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Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol2013; 108:656.

Refractory CD

• Type 1

• Lymphocyte infiltration similar to untreated CD

• May require immunosupression

• 5 year survival 93%

• Type 2

• Clonal expansion of intraepithelial lymphocytes and an aberrant phenotype lacking CD3, CD8, and T-cell receptors

• 5 year survival 44%

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TTG levels

• Italian study of 2245 patients over 5 years with annual anti-tTG

• Proportion of patients with negative tTG progressively increased from 83% to 93% during the 5-year follow-up

• Affected by• Poor adherence to gluten-free diet (HR 4.764)

• Long duration of gluten-free diet (HR 0.929)

• Female gender (HR 1.472) were independently associated with serological outcome

• In individual patients, 69% were “persistently negative”, 1% “persistently positive” and 30% “intermittently negative or positive”

• In a US study, the median time from onset of GFD to achieve mucosal healing was 3 years

• Could consider a follow-up biopsy in adults after 2 years of starting a GFD to assess for mucosal healing

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Resources

• Referral to dietitian

• Canadian Celiac Association • www.celiac.ca

• Food choices, labeling, cross contamination, recipe adaptation, advice on social situations

• Links to local chapters

Take home points

• Keep a high index of suspicion as symptoms are variable, and can affect patients of all ages and ethnicities

• Remember to order an IgA in case there is a deficiency

• Optimal to obtain biopsies on a gluten containing diet

• HLA DQ2 and DQ8 have a very high NPV (>99%)

• By 6 – 12 months 80% of patients will be negative

• If recurrent symptoms, review diet, check serology, consider refractory CD

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