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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