20180428 1030 Murray Celiac Disease (3)
Transcript of 20180428 1030 Murray Celiac Disease (3)
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Celiac Disease
Joe Murray
ObjectivesBe able to
1. Select the appropriate tests for celiac disease diagnosis
2. Describe the challenge to diagnosis when a patient starts on a gluten free diet before testing
3. Plan the management of newly diagnosed and non-responsive celiac disease.
Case• 47 year old female with recent severe autoimmune
hepatitis presents with worsening arthralgias after taper of steroids
• 15 year history of: • low back pain, • Chronic fatigue and mild cognitive impairment• Started after birth of her child
• Hx of primary hyperparathyroidism,
• ANA+, RF -, Hemoglobin 13.1, ferritin 38
• Rx Fentanyl patch, Zoloft, Adderall, naproxen
• No digestive symptoms
Case: PolyarthralgiaWould you:
1. Start a PPI 2. Send for physical
therapy3. Refer for chronic
pain management4. Restart steroids5. Do a tissue
transglutaminase IGA
Case• Tissue transglutaminase IgA >100 AU ( NR < 4)
• Biopsy: total villous atrophy
• Arthralgias resolved
• Hepatitis did not recur
• Hyperparathyroidism resolved
• Fatigue improved
• Reduction in narcotics
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What is Celiac Disease?
• It is a inflammatory state of the small intestine that occurs in genetically predisposed individuals and resolves with exclusion of dietary gluten.
CeliacDisease
The “Old” Disease
• A rare disorder typical of infancy
• Everyone had diarrhea/steatorrhea
• Wide incidence fluctuations in space (1/400 Ireland to 1/10,000 Denmark) and in time
• A disease of essentially European origin
• That was rare in North America
Talley, AJG,1994
The Old Celiac Disease 1990’s
Steatorrhea
Osteoporotic Fracture in a 36 y.o. Male
• Sledding injury• Osteoporosis
( L-Spine t-score < -4)• No GI symptoms • No deficiencies
• Meets an astute clinician• TTg-IGA +• Biopsy: total villous atrophy
Iron-Deficiency Anemia
• 5-8% of adults with unexplained iron deficiency anemia have Celiac Disease
• Often Resistant to Oral Fe
• 5-15% of patients undergoing endoscopy for iron deficiency anemia
• 4% of Caucasians with iron deficiency
• Other hematological features:
• Macrocytic anemia ( B12)
• Hyposplenism Vogelsang, 98; Grisolano, 2004Murray CGH 2014,
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Dermatitis Herpetiformis
• Erythematous macule > urticarial papule > tense vesicles
• Severe pruritus
• Symmetric distribution
• 90% no GI symptoms
• 75% villous atrophy
• Gluten sensitive
Garioch JJ, et al. Br J Dermatol. 1994;131:822-6.Fry L. Baillieres Clin Gastroenterol. 1995;9:371-93.
Reunala T, et al. Br J Dermatol. 1997;136-315-8.
Recurrent Aphtous Stomatitis
By permission of C. Mulder, Amsterdam (Netherlands)
Abnormal Liver Blood Tests
• Incidental elevated serum transaminases (ALT, AST)
Up to 9% may have silent celiac disease
Liver biopsies in these patients showed non-specific reactive hepatitis
Liver enzymes normalize on gluten-free diet
• Occasionally severe hepatitis
Rubiotapia et al, Hepatology, 2007
Abnormal Liver Tests in Patientswith Celiac Disease
Reference Cases
Abnormal LiverTests (%)
Responses to a Gluten-
Free Diet (%)*
Hagander et al (Lancet 1977;2:270-2) 53 39 N/A
Bardella et al (Hepatology 1995;22:833-6) 158 42 95
Bonamico et al (Minerva Pediatr 1986;38:959-63) 65 57 N/A
Novacek et al (Eur J Gastroenterol Hepatol1999;11:283-8)
176 40 96
Jacobsen et al (Scand J Gastroenterol 1990;25:656-62)
171 47 75
N/A indicates not available.*The response was defined by complete normalization of the liver tests.
From Rubio-Tapia A and Murray JA, Hepatology 2007;46:1650-8.
Reproductive Effects
• Infertility in men and women*
• Increased rate of spontaneous abortion
• Delayed menarche
• Early menopause
• Reversible with gluten free diet
*Choi et al, J Reprod Med, 2012
In: Mayo Clinic: Going Gluten Free
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What Triggers Disease in Susceptible Individuals?
Celiac Disease
Gluten GeneticsNecessaryCauses
SexInfant feedingInfections*Microbiome
C-section#
Risk Factors
Pathogenesis?TTG
*Rotavirus at weaning Stene et al, AJG 2006*Gastroenteritis in Adults Riddle et al. AJG 2012
#Pregnancy outcome and risk of celiac disease Marild et al. Gastro, 2012
Can Celiac Disease be Prevented by Manipulating Infant Feeding?
• Breastfeeding
• Delayed Intro of gluten
• Overlap gluten with
breastfeeding
• Infections
• Genetic risk
CeliPrev Study: Italy
Trial of Induction of Tolerance with Low-dose Gluten in Children at Risk
Vriezinga SL et al. N Engl J Med 2014
Can We Prevent Celiac Disease
• Breastfeeding
• Delayed Intro of gluten
• Overlap gluten with
breastfeeding
NEJM, October 2014
NO!
But we can detect it
Diagnostic Guidelines Galore
DIAGNOSTIC CRITERIA• Symptoms of, or risk for, celiac disease
• Celiac Serology is an initial detection test and adjunct to diagnosis
• Villous atrophy with chronic inflammation in the proximal small intestine while eating gluten*
• Objective clinical response to a gluten free diet
AGA 2006, ACG 2013, WGO 2013BSG, 2014
* IELS with Serology+
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@The Mayo Clinic 2013
Serology Tests Available 2017
Test Sensitivity Specificity
Gliadin Ab <80% ~80%
Endomysial Ab
90-97% 99-100%
tTGA 90-98% 90-98%
DGP* 84% >90%
Rostom A, et al. Gastro 2006
*Rashtak S, et al. CGH 2008
* Deamidated gliadin peptide IGG good in IgA def.
Celiac Cascade
© 2014 Mayo Foundation for Medical Education and Research. All Rights Reserved.
Department of Laboratory Medicine and Pathology
Diagnostic Challenge of Celiac DiseaseSerology Algorithm
Normal IgA Zero IgA
Low IgA
Celiac Disease Serology Cascade • Immunoglobulin A (IgA)
Anti-TTG, IgA
• Endomysial antibodies, IgA • Anti-deamidated gliadin, IgA
• Anti-TTG, IgA and IgG • Anti-deamidated gliadin,
IgA and IgG• Anti-TTG, IgG • Anti-deamidated gliadin, IgG
• Anti-TTG, IgA
• Anti-deamidated gliadin, IgA• Interpretive comment
Interpretive report includes: • Immunoglobulin A (IgA)
• Endomysial antibodies, IgA
Positive ornegative
Weak positive
Selective IgA Deficiency
and IgG
and IgG
IgG
IgG
Normal Intestine Celiac Disease
4+
1-2
Evans et al, 2011
Stage 1 Stage II Partial atrophy IIIa
Partial atrophy IIIb Partial atrophy IIIc Total atrophy
Gold Standard: Small Bowel BiopsyHorvath
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New ESPGHAN Guidelines for Coeliac Disease:Can we Avoid the Diagnostic Biopsy?
• Biopsy can be avoided if all of the following apply:
• Symptoms suggestive of CD • tTg-IGA > 10 x upper limit of normal then: separate blood sample• EMA+ • HLA = DQ2 or DQ8• Responds to gluten diet
Celiac disease provenBiopsy avoided!
Husby S, et al. J Pediatr Gastroenterol Nutr, 2012
SPECIFICITY of tTg-IGA
3-10 x ULN
Husby and Murray: Nature Reviews Gastroenterology and Hepatology 2014
Increasing titers of tTg-Iga Antibodies predicts increasing certainty of the presence of
Celiac Disease
Adult GI Response to Pediatric GI
British Society of Gastroenterology Guidelines 2014
Just go on a diet and if you are better, you probably have sprue.
What About Patients on GFD Diet?
What About Patients on GFD Diet?
Often unhappy patient
Serology and biopsies can normalize
HLA type ( celiac gluten free cascade)
Challenge
Some patients will not eat gluten
Why argue with success if diet is nutritionally adequate?
Often unhappy patient
Serology and biopsies can normalize
HLA type ( celiac gluten free cascade)
Challenge
Some patients will not eat gluten
Why argue with success if diet is nutritionally adequate?
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Decrease in Sensitivity of ELISA Tests After Treatment with GFD
*P<0.05*P<0.05
**P<0.0001**P<0.0001
Sen
siti
vity
Sen
siti
vity
AGA II AGA II AGA II AGA AGA TTG TTGIgA IgG IgA+G IgA IgG IgA IgG
AGA II AGA II AGA II AGA AGA TTG TTGIgA IgG IgA+G IgA IgG IgA IgG
On GlutenOn Gluten Gluten Free Gluten Free
**** ****
****
****
****
******
Test before treatment! NB: IgA deficiency in 3%
Gluten ChallengeGluten Challenge Adequate gluten for long enough to
develop gut lesions
Make them sick
1 slice of wheat bread daily for 6 weeks
Then do serology biopsy if positive
Some delayed responders
If negative serum and no symptoms at 6 weeks Continue challenge to 12 weeks
Adequate gluten for long enough to develop gut lesions
Make them sick
1 slice of wheat bread daily for 6 weeks
Then do serology biopsy if positive
Some delayed responders
If negative serum and no symptoms at 6 weeks Continue challenge to 12 weeks
Leffler et al. Gut 2012
Celiac Disease And HLA RiskCeliac Disease And HLA Risk
Genetic TestsBig Limitation
Genetic TestsBig Limitation
• HLA type does not equal disease
• Most people with the at-risk types will nothave celiac disease
• 2/3rds of family members will carry the at-risk types but most don't get the disease
• 50% of type 1 diabetes have the same HLA type but only 6% get CD
• HLA type does not equal disease
• Most people with the at-risk types will nothave celiac disease
• 2/3rds of family members will carry the at-risk types but most don't get the disease
• 50% of type 1 diabetes have the same HLA type but only 6% get CD
Schuppan D: Gastroenterology, 2000Kauikinen K: Am J Gastroenterol, 2002Schuppan D: Gastroenterology, 2000Kauikinen K: Am J Gastroenterol, 2002
CP1293145-39
New York Times February 4, 2013
Non-Celiac Gluten Sensitivity
The term NCGS relates to one or more of a variety of immunological,
morphological or symptomatic manifestations
precipitated by the ingestion of gluten in people in whom
CD has been excluded.
Missing: no alternative explanation Ludvigsson JF, Leffler DA, Bai JC, et al. Gut (2012).
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T42
Gluten Sensitive GI Symptoms“Celiac Like”
“Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial”.
Biesiekierski JR et al. AJG 2011T45
Follow Up Study
Self declared gluten sensitive Repeat trial Run in with Low FODMAPs All symptoms disappeared No response to gluten Not Gluten?? Only 8% responded to Gluten
Biesiekierski JR et al. Gastro 2013
FODMAPSNot gluten
A Controlled Trial of Gluten-Free Diet in PatientsWith Irritable Bowel Syndrome-Diarrhea
• GFD reduced BMs, improved stool form in DQ2+ subjects
Vazquez–Roque et al. Gastro, 2013
Markers of intestinal epithelial cell damage and systemic immune activation in response to the Gluten free diet.
Melanie Uhde et al. Gut doi:10.1136/gutjnl-2016-311964
Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.
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T48
• Weak evidence for Non celiac Gluten sensitivity• Diagnosis of exclusion• Ok to try GFD if testing for celiac done already
Mayo Clinic: on Going Gluten free
©2015 MFMER | slide-49
Changes of prevalence and proportions of gluten related disorders between 2009 and 2014
PWAGUndiagnosed CDDiagnosed CD
Prevalence of gluten related disorders
1.3 % (95% CI, 0.9-1.6)
Prevalence of gluten related disorders
1.8 % (95% CI, 1.2-2.4)
Prevalence of gluten related disorders
2.4 % (95% CI, 1.4-3.4)
2009-2010
2011-2012
2013-2014
Case: 64 Year Old Female
• Gradual onset of diarrhea, weight loss weakness
• Hospitalized several times over 12 months
• History of hypertension on olmesartan
• Total villous atrophy
• Serology not done initially now negative
• No response to GFD
• Responded to 40 mgs of prednisone
• Started on Azothiaprine
Refractory Celiac Disease64 year old female with presumed refractory celiac disease doing okay on budesonide? What do you do now
1. Stay on current therapy
2. Taper and attempt to stop Budesonide
3. Review dietary adherence
4. Stop olmesartan
5. Ct Scan for Lymphoma
Refractory Celiac Disease
• 64 year old female with refractory celiac disease/ collagenous sprue doing okay on budesonide? What do you do now
1. Stay on current therapy
2. Taper and attempt to stop Budesonide
3. Review dietary adherence
4. Stop olmesartan
5. Ct Scan for Lymphoma
Follow up Follow up
• On Olmesartan for 8 years
• Stopped the drug
• Off steroids and off GFD
• Healed intestine
• Diagnosis: Drug induced enteritis
• On Olmesartan for 8 years
• Stopped the drug
• Off steroids and off GFD
• Healed intestine
• Diagnosis: Drug induced enteritis
Rubio-tapia et al: MCP 2013
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False Positive Biopsies
• Poorly oriented “ flattened biopsies”
• NSAIDS
• Self-limited enteritis in 7 adults Goldstein, Am J Clin
Path 2004
• Tropical sprue ( travel history)
• Combined variable immunoglobulin deficiency
• Autoimmune enteropathy Akram et al. CGH 2007
• Non granulomatous enterocolitis
Biopsy First?
Duodenal biopsyWith Villous
Atrophy
TTG- IgA
? other diseasesReview biopsiesHLATrial of GFD
IgA deficient
Negative Positive
No Yes
TTG-IgG Gluten-free diet PositiveNegative
Treatment
• Only treatment for celiac disease is a gluten-free diet (GFD)
•Strict, lifelong diet
•Avoid•Wheat
•Rye
•Barley
Management Plan
• Explain the disease
• Strongly advocate a gluten free diet
• Refer to expert dietitian
• Check bone density
• Identify and treat deficiencies
• Calcium and vitamin D replacement
• Vaccine non-response
• Hyposplenism
Treatment of Celiac Disease
• Strict gluten free diet is the only accepted treatment for celiac disease
• The GFD is one of the more challenging treatments we assign patients
• Involves avoidance of all wheat, rye and barley (including malt) products
• Less than 50 mg of gluten (1/30th of a slice of bread) can cause significant, sustained mucosal inflammation
• Gluten free oats are ok for most
GFD
1Catassi (2007;85:160-6)
Dangers of Non-Compliance
• Increased mortality Holmes et al. 1989 Corrao et al.
• Osteoporosis Cellier
• Lymphoma Holmes et al.
• Other cancers Green, 2006
• Psychological effects hallert
• Failure to heal RubioTapia, 2010
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How Are Adherence and Response toa Gluten-Free Diet Measured?
• Dietitian review
• Celiac Disease adherence test (CDAT)
• Drop in serology (insensitive)
• Detection of gluten intake• Stool, urine, blood ( in
development)
Follow Up Of Celiac Disease
• Symptoms resolve in 1-3 months
• Serology level fall substantially in 6 months
• Biopsies improve more slowly in adults than children
• Re-biopsy in 1-2 years (optional)
• Dietitian follow up for compliance
• MD interest is crucial
Other include:Peptic ulcer diseaseCrohn’s diseaseDuodenal adenoCAFood allergy GastroparesisPancreatic Insufficiency
22Leffler (2007;5:445-50), 23Adulkarim (2002;97:2016-21)
Causes of Non‐Responsive Celiac Disease
Persistent or recurrent signs/symptoms occur in
~10-30% of patients
Key Points
• Celiac disease is common (~1%)
• Test before treatment!• Celiac serology cascade
• Strict gluten free diet (lifelong)
• Follow it up
• Non-celiac gluten sensitivity is controversial, heterogeneous and probably real
• Not everything that flattens is celiac disease
Missed Opportunities
• Diminished Infertility Pre-diagnosis Zugna, et al. Gut 2010
• Long years of unexplained symptoms
• Long delay in diagnosis Green AJG, 2001
• Osteoporosis is common and may never regain bone mass. Risk of fractures persists after diagnosis. Jafri et al, DDS 2007
• Health care savings Long et al,APT 2010 and Green et al. 2008