Should we Screen for Celiac Disease in IBS?

Brennan Spiegel, MD, MSHS

Dietary factorsHigh sorbitol diet

High-fiber dietFODMAP Diet

Caffeine Alcohol

InflammationUlcerative colitisCrohn’s disease

Microscopic colitis

EndocrineHyperthyroidism

DiabetesCarcinoid

Gastrinoma

Psychological

AnxietySomatizationDepression

PTSD

InfectionSIBOC. diff

Giardiasis

MalabsorptionCeliac sprue

Carb intolerancePancreatic disease

Bile acid malabsorption

Existential Question: What Is IBS?

IBS

Is IBS an absence of other things?

Or is it some thing… unto itself?

IBS

InflammationAltered brain–

gut interactions

Visceral hypersensitivity

Geneticfactors

Psychosocialfactors

Bacterial-Host Interactions

IBSIBS

Proposed Pathophysiological Mechanisms Involved in IBS

IBS Celiac

How often is overlap?When to screen?

How to screen?

Patient C.M. Case History

• 34 year old woman with 10-years of loose stools

• 4-6 bowel movements per day

• LLQ crampy pain that improves with stool passage

• Always feels “bloated”

• No weight loss, nighttime symptoms, incontinence, fevers, vomiting, or rectal bleeding

• No dairy intolerance, unusual travel, acute GI illnesses, recent antibiotics or other relevant meds

• No alarm features on physical examination

Patient C.M. – Laboratories

• Normal studies included:

– Complete blood count

– Serum electrolytes

– Stool cultures, sensitivity, and leukocytes

– Stool occult blood

– Erythrocyte sedimentation rate

– C Reactive Protein

Patient C.M. – Treatment Course

• Treated with antispasmodics

No improvement, felt sleepy

• Treated with rifaximin

“Little better at first, then worse again”

• Treated with loperamide

Diarrhea improved, but still had abdominal pain

“My IBS went away once I started the gluten free diet. And then, soon after trying bread again, it all came back.”

Clinical Questions

• Does she have celiac disease (CD), gluten sensitivity, or both?

• Does gluten exposure explain her symptoms?

• Could she still have IBS in addition to CD?

• Is a gluten-free diet appropriate at this point?

• What about gluten challenge, then re-biopsy?

• Need to check HLA-DQ2 or HLA-DQ8?

IBS Celiac

100% have symptoms consistent with celiac

20-75% have symptoms consistent with IBS

Zipser RD, et al. Dig Dis Sci 2003;48:761O’Leary C, et al. Am J Gastro 2002;97:1463

InflammationSIBO

IBS

66% have SIBO15-80% have SIBO

Tursi A, et al. Am J Gastro 2003;98:839

O’Leary C, Quigley E. Am J Gastro 2003;98:720

Verdu E, et al. Am J Gastro 2009

Celiac

Is this just a case of “true, true, and

unrelated?”

Is this just a case of “true, true, and

unrelated?”

Clinical Spectrum – Definitions

Overt celiac: Positive serology with Marsh III lesion.

Latent celiac: Normal serology and mucosa despite gluten, but genetic predisposition for sprue, persistent underlying immunologic abnormalities, with potential to express overt celiac with gluten challenge.

Gluten sensitivity: Minimal enteropathy (Marsh I-II) that improves histologically and symptomatically to gluten withdrawal in a patient with HLA DQ positivity

Wahnschaffe U, et al. Gastro 2001;1329Weinstein W. Gastro 1972;66:489

Verdu E, et al. Am J Gastro, 2009

Serology + Serology -

Villlous Blunting

No Villous Blunting

Simplified Sprue 2x2 Table

Overt Sprue

1. Latent Sprue2. False Pos Serology3. False Neg Biopsy

False Negative(or other Dx)

1. No Sprue2. Latent Sprue3. Gluten sensitivity

More Realistic Sprue Table

TTG –AGA -

TTG –AGA +

TTG +AGA -

TTG +AGA +

Marsh0

Marsh I-II

Marsh III

1. No Sprue2. Latent Sprue

1. Gluten sens.2. False Pos AGA

Overt Sprue

1. Latent Sprue2. False Pos AGA

& TTG

1. Latent Sprue2. False Pos

Gluten sens.1. Gluten sens.2. False Neg

1. Other Dx2. False Neg

1. Overt Sprue2. Other Dx with FP

AGA

1. Gluten sens.2. False Pos TTG

Overt Sprue

1. No Sprue2. Latent Sprue

Pre-T

est L

ikel

ihood

Low

Med

ium

High

HistologyMarsh 0 Marsh IIMarsh I Marsh III

Ser

olo

gy

-/-

+/-

-/+

+/+

Clinical Reality: the Sprue Cube

Biopsy-Proven Celiac Disease in IBS: Results of Meta-Analysis

Ford A, Chey W, Talley N, Malhotra A, Spiegel B, Moayyedi P. Arch Int Med 2009;13:169

It is cost-effective to screen for celiac sprue in IBS if pre-test likelihood exceeds 1%

Spiegel et al. Gastroenterology 2004;126:1721

It is cost-effective to screen for celiac sprue in IBS if pre-test likelihood exceeds 1%

Spiegel et al. Gastroenterology 2004;126:1721

Data from U.S. – Link is Weaker

Cash et al. Gastroenterol 2011;141:1178

Biopsy proven sprue in IBS: 0.41%

Patient C.M. – Continued

• Reluctant to diagnose celiac disease

– Only Marsh I lesion

– Anti-TTG negative 98% NPV

– Anti-GA equivocal

– Lifetime diagnosis has significant implications

• Opted for gluten challenge with re-biopsy with HLA testing

– Cannot yet rule-out gluten sensitivity

Patient C.M. – Continued

• Enteroscopy with duodenal and jejunal biopsies normal after 2 month gluten challenge

• Follow-up labs

– ESR / CRP normal

– CBC normal

– IBD Panel negative

– HLA-DQ2 positive, HLA-DQ8 negative

Prometheus Sprue Panel

Does she have gluten sensitivity?

Latent Sprue and Gluten Sensitivity in IBS

• Wahnschaffe et al. studied 102 IBS patients:

– 0% had positive antibodies in serum– 35% were HLA-DQ2 +– 23% had elevated IELs (Marsh I), none Marsh II+– 30% had positive anti-TTG IgA in duodenal aspirate

• Treated sub-set with gluten-free diet

– Compared to controls, GFD improved stool frequency in HLA+ and duodenal anti-TTG+ patients

– Elevated IELs did not predict symptom response

Wahnschaffe U, et al. Gastro 2001;1329

D-IBS Patients: Predicting Response to Gluten-Free diet

Wahnschaffe U, et al. CGH 2007;5:844

Profile PPV NPV

DQ2 + 44% 94%

Antibody + (AGA/TTG)

45% 86%

DQ2+ and Ab+ 56% 88%

Impact of Gluten on EMA Positive Patients with Marsh I-II Lesions

Kurppa K, et al. Gastroentrol 2009;136:816-823

Impact of Gluten on Symptoms

Kurppa K, et al. Gastroentrol 2009;136:816-823

• Patients with mild enteropathy and positive serologies may benefit from early treatment with a gluten free diet even if they don’t meet strict criteria for celiac disease

• Current diagnostic criteria for celiac disease may need to be expanded to include patients with mild enteropathy (Marsh I-II)

• Patients with mild enteropathy and positive serologies may benefit from early treatment with a gluten free diet even if they don’t meet strict criteria for celiac disease

• Current diagnostic criteria for celiac disease may need to be expanded to include patients with mild enteropathy (Marsh I-II)

What About if Negative Serologies?

Vazquez-Roque, et al. Gastroentrol 2013;144:903-911

Patient C.M. – Continued

• Has been on strict gluten-free diet for 6 years, and has remained considerably better but still has some “IBS symptoms with stress.”

Take Home Messages

• Non-U.S. IBS patients around 4x more likely to harbor underlying biopsy-proven celiac disease

• Testing for celiac cost-effective if pre-test likelihood exceeds 1% – but probably lower in U.S.

• Even if no celiac disease, may still harbor latent celiac disease or gluten sensitivity

• If borderline, consider checking HLA DQ2 – if negative, probably no celiac; if positive, consider GFD