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ACG Postgraduate Course Copyright 2012 ACG

October 2012 1

Celiac Disease and Gluten Sensitivity: New Tests and

Approaches

Celiac Disease and Gluten Sensitivity: New Tests and

ApproachesApproachesApproaches

Joseph A MurrayJoseph A MurrayJoseph A Murray

Mayo Clinic, Rochester, MN

Joseph A Murray

Mayo Clinic, Rochester, MN

DISCLOSUREDISCLOSURERelevant Financial Relationship(s)

Alba Therapeutics: grant support

Relevant Financial Relationship(s)Alba Therapeutics: grant supportAlba Therapeutics: grant support

Alvine Inc: Advisory Board

Consultant: Ferring, Ironwood, Bayer, Flamentera, Arteille, Actiogenix, Shire,

NexPep

Alba Therapeutics: grant support

Alvine Inc: Advisory Board

Consultant: Ferring, Ironwood, Bayer, Flamentera, Arteille, Actiogenix, Shire,

NexPep


October 2012 2

What is the connection between these ?

What is the connection between these ?

IntroductionIntroduction

• Celiac disease is well defined• Celiac disease is well defined• Celiac disease is well defined disease

• Non-Celiac Gluten sensitivity is not so well defined

• May share common pathways to

• Celiac disease is well defined disease

• Non-Celiac Gluten sensitivity is not so well defined

• May share common pathways to ay s a e co o pat ays tosymptoms

ay s a e co o pat ays tosymptoms


October 2012 3

What is Celiac Disease?What is Celiac Disease?

• It is a inflammatory state of the small intestine that occurs in genetically

• It is a inflammatory state of the small intestine that occurs in geneticallyintestine that occurs in genetically predisposed individuals and resolves with exclusion of dietary gluten.

intestine that occurs in genetically predisposed individuals and resolves with exclusion of dietary gluten.

Normal CeliacDisease

PathogenesisPathogenesis

Genetics Gluten NecessaryCausesCauses

GenderInfant feedingInfections*OthersPathogenesis

?

Celiac disease

Risk Factors

*Rotavirus at weaningGastroenteritis in Adults

Stene et al, AJG 2006Riddle et al. AJG 2012


October 2012 4

Presentations of Celiac DiseasePresentations of Celiac Disease

• Classic malabsorptive syndrome( 25%)• diarrhea, steatorrhea, weight loss, multiple deficiencies

• Classic malabsorptive syndrome( 25%)• diarrhea, steatorrhea, weight loss, multiple deficiencies

• Monosymptomatic ( 50%)• Anemia, diarrhea, lactose intolerance, constipation

• Acute Abdomen ( rare)• abdominal pain, intussception, vomiting, obstruction

perforation, lymphoma

• Non-GI presentations(25% )

• Monosymptomatic ( 50%)• Anemia, diarrhea, lactose intolerance, constipation

• Acute Abdomen ( rare)• abdominal pain, intussception, vomiting, obstruction

perforation, lymphoma

• Non-GI presentations(25% )p ( )• Infertility, bone disease, neurological disease, short stature,

brittle diabetes, chronic fatigue, abnormal LFTS

p ( )• Infertility, bone disease, neurological disease, short stature,

brittle diabetes, chronic fatigue, abnormal LFTS

Fe-Deficient AnemiaResistant to Oral FeFe-Deficient AnemiaResistant to Oral Fe

• Most common non-GI manifestation in some studies

• Most common non-GI manifestation in some studiessome studies

• 5-8% of adults with unexplained iron deficiency anemia have Celiac Disease

• 5-15% of patients undergoing endoscopy for fe deficiency anemia have celiac disease

some studies

• 5-8% of adults with unexplained iron deficiency anemia have Celiac Disease

• 5-15% of patients undergoing endoscopy for fe deficiency anemia have celiac disease V l 98 G i l 2004

Murray, CGH, 2003

have celiac disease

• 30-50% of patients getting EGD for anemia do not get duodenal biopsies!

have celiac disease

• 30-50% of patients getting EGD for anemia do not get duodenal biopsies!

Vogelsang, 98; Grisolano, 2004

Harewood, 2003


October 2012 5

Celiac Disease: Acute AbdomenCeliac Disease: Acute Abdomen

• Mimic partial• Mimic partial• Mimic partial small bowel obstruction

• Perforation

• Stricture

L h

• Mimic partial small bowel obstruction

• Perforation

• Stricture

L h• Lymphoma

• Intussusception

• Lymphoma

• Intussusception

• 12/169 patients with recurrent• 12/169 patients with recurrent

Recurrent PancreatitisRecurrent Pancreatitis

• 12/169 patients with recurrent idiopathic pancreatitis had celiac disease

• Papillary stenosis on manometry

• Pain responded to ERS and GFD

• 12/169 patients with recurrent idiopathic pancreatitis had celiac disease

• Papillary stenosis on manometry

• Pain responded to ERS and GFDa espo ded to S a d Ga espo ded to S a d G

Patel et al , GE Endoscopy, 1999


October 2012 6

Abnormal Liver Blood TestsAbnormal Liver Blood Tests• Incidental elevated serum

transaminases (ALT, AST)

• Up to 9% may have silent Celiac

• Incidental elevated serum transaminases (ALT, AST)

• Up to 9% may have silent Celiac• Up to 9% may have silent Celiac Disease

• Liver biopsies in these patients showed non-specific reactive hepatitis

Liver enzymes normalize on gluten-

• Up to 9% may have silent Celiac Disease

• Liver biopsies in these patients showed non-specific reactive hepatitis

Liver enzymes normalize on gluten-• Liver enzymes normalize on gluten-free diet

• Occasionally severe liver disease

• Liver enzymes normalize on gluten-free diet

• Occasionally severe liver diseaseRubio-Tapia et al. Liver international, 2008

RubioTapia and Murray, Hepatology, 2007

Who Gets Celiac Disease?Who Gets Celiac Disease?

• Adults >> children, female > males• Adults >> children, female > males

• Worldwide, mostly Caucasians

• Any age including elderly

• People with other immune disorders• Type one diabetes mellitus

• Sjogren’s syndrome

• Worldwide, mostly Caucasians

• Any age including elderly

• People with other immune disorders• Type one diabetes mellitus

• Sjogren’s syndrome• Sjogren s syndrome

• Thyroid disease

• Lupus, Addison’s disease

• Family members of celiacs

• Sjogren s syndrome

• Thyroid disease

• Lupus, Addison’s disease

• Family members of celiacs


October 2012 7

How Common in the United States?How Common in the United States?

www.2010.census.gov

The Prevalence of Celiac DiseaseThe Prevalence of Celiac Diseasein the United Statesin the United States

The Prevalence of Celiac DiseaseThe Prevalence of Celiac Diseasein the United Statesin the United States

Alberto Rubio-Tapia, Jonas F. Ludvigsson,

Tricia L. Brantner, Joseph A M rra James E

Alberto Rubio-Tapia, Jonas F. Ludvigsson,

Tricia L. Brantner, Joseph A M rra James EA. Murray, James E.

Everhart

Mayo Clinic and NIDDK*

A. Murray, James E. Everhart

Mayo Clinic and NIDDK*


October 2012 8

Assessment of Celiac Disease Status

Assessment of Celiac Disease Status

• Direct Interview (two structured questions):• Has a doctor or other health professional ever

• Direct Interview (two structured questions):• Has a doctor or other health professional everHas a doctor or other health professional ever

told you that you have celiac disease?

• Are you on a gluten-free diet?

• Serology testing: coded serum specimens shipped to celiac disease research

Has a doctor or other health professional ever told you that you have celiac disease?

• Are you on a gluten-free diet?

• Serology testing: coded serum specimens shipped to celiac disease research laboratory at Mayo Clinic and tested between Jan 2009 and Jan 2011laboratory at Mayo Clinic and tested between Jan 2009 and Jan 2011

Gluten Free Diet Gluten Free Diet

Prevalence of Celiac Disease and Gluten Free Diet: NHANES 2009-2010

Celiac DiseaseCeliac Disease

Diagnosed CD

GFD without Dx of CD

Untreated CD17%

83%

RubioRubio--Tapia, et al. AJG 2012 .Tapia, et al. AJG 2012 .

1.6 million 1.8 million1% of Caucasians


October 2012 9

World Map Indicating Prevalence of Celiac DiseaseWorld Map Indicating Prevalence of Celiac Disease

CP1253156-1

~1% 1-2% >2% <0.5% Report of cases N/A

Remes-Troche JM. Ramirez-Iglesias MT. Rubio-Tapia A. Alonso-Ramos A. Velazquez A. Uscanga LF.

Journal of Clinical Gastroenterology. 40(8):697-700, 2006

How Do You Find It?How Do You Find It?

Diagnostic TestsDiagnostic Tests


October 2012 10

Duration Of Symptoms Before Diagnosis

Duration Of Symptoms Before Diagnosis

Stoven et al. Poster, P154 ACG 2012

Detection versus DiagnosisDetection versus Diagnosis

• Detecting CD is the not the same as• Detecting CD is the not the same as• Detecting CD is the not the same as confirming it!

• For detection you do not want to miss a case; maximize sensitivity

• For diagnosis you need confirmation: maximize specificity

• Detecting CD is the not the same as confirming it!

• For detection you do not want to miss a case; maximize sensitivity

• For diagnosis you need confirmation: maximize specificitymaximize specificity

• Traditionally serology first then biopsy

maximize specificity

• Traditionally serology first then biopsy


October 2012 11

Diagnostic Criteria Diagnostic Criteria

• Villous atrophy with chronic inflammation in the proximal small intestine while eating gluten*

• Villous atrophy with chronic inflammation in the proximal small intestine while eating gluten*gluten

• Objective clinical response to a gluten free diet

• Serology provides important supportive evidence

ESPHGAN i d id li A id

gluten

• Objective clinical response to a gluten free diet

• Serology provides important supportive evidence

ESPHGAN i d id li A id• ESPHGAN revised guidelines - Avoid Biopsy in some children?

• ESPHGAN revised guidelines - Avoid Biopsy in some children?

ESPHGAN Guidelines 1991UEDW Guidelines 2001AGA 2006

*IELS with Serology+

Comparison of Serological Tests

Comparison of Serological Tests

Test Sens Spec Tech Cost

HtTg 96-98 88-100 Low $$

EMA 75-98 99-100 High $$$$

Gliadin-IgA 53-100 65-100 Low $

Gliadin-IgG 57-100 42-98 Low $


October 2012 12

Comparison of Serological TestsComparison of Serological Tests

Test Sens Spec Tech Cost

HtTg 96-98 88-100 Low $$

EMA 75-98 99-100 High $$$$

Gliadin-IgA 53-100 65-100 Low $

Gliadin-IgG 57-100 42-98 Low $

DeamidatedGliadin P

80 95 Low $

Sensitivity of TTg-IGA Sensitivity of TTg-IGA


October 2012 13

Decrease in Sensitivity of ELISA Tests After Treatment with GFD

Decrease in Sensitivity of ELISA Tests After Treatment with GFD

80 8084

100GCDGCDGCDGCD GFDGFDGFDGFD

******** ******** ********

Sen

siti

vity

Sen

siti

vity

80

66

80

69

42

3434

17

37

24

16 1720

40

60

80 ****************

************

*P<0.05*P<0.05*P<0.05*P<0.05

**P<0.0001**P<0.0001**P<0.0001**P<0.0001

17

8

16 17

0

20

AGA IIAGA II AGA IIAGA II AGA IIAGA II AGAAGA AGAAGA TTGTTG TTGTTGIgAIgA IgGIgG IgA+GIgA+G IgAIgA IgGIgG IgAIgA IgGIgG

AGA IIAGA II AGA IIAGA II AGA IIAGA II AGAAGA AGAAGA TTGTTG TTGTTGIgAIgA IgGIgG IgA+GIgA+G IgAIgA IgGIgG IgAIgA IgGIgG

New ESPGHAN GuidelinesNew ESPGHAN Guidelines• Biopsy can be avoided if all of

the following apply:• Biopsy can be avoided if all of

the following apply:• tTg-IGA > 10 x upper limit of

normal

• Symptoms suggestive of celiac disease

• EMA+ (on a new blood sample)

• tTg-IGA > 10 x upper limit of normal

• Symptoms suggestive of celiac disease

• EMA+ (on a new blood sample)( p )

• HLA = DQ2 or DQ8

• Responds to gluten diet

( p )

• HLA = DQ2 or DQ8

• Responds to gluten diet

Husby et al, JPGN 2012Highly Controversial!


October 2012 14

Can Serology Replace Biopsy? Can Serology Replace Biopsy?

How Good is Serology in PracticeHow Good is Serology in Practice

• Specificity of the tests

• TTg-IGA high >95%

• Specificity of the tests

• TTg-IGA high >95%

• EMA-IGA high 76*-100%

• Variability:• Lab to lab

• EMA-IGA high 76*-100%

• Variability:• Lab to lab

• Kit to kit

• Reference ranges

• Performance

• Kit to kit

• Reference ranges

• Performance

* Mubarak et al, JPGN 2011


October 2012 15

“A Biopsy Is Not Always Necessary to Diagnose Celiac Disease”

“A Biopsy Is Not Always Necessary to Diagnose Celiac Disease”

Accuracy of High Titer Results

Specificity (%)

Sensitivity(%)

PPV(%) NPV(%)

EMA-IGA 66 96 79 93

TTg-IGA >10 83 96 88 93

y g

TTg-IgA >100 97 76 97 75

Mubarak et al. JPGN., May 2011.

Issues:Retrospective study of real clinical practiceEffect of serum testing prior to scope!Low accuracy of EMA

PhilosophyPhilosophy

• Is a blood test a solid enough• Is a blood test a solid enough• Is a blood test a solid enough foundation upon which to build a lifetime of treatment for a patient?

• Should CD be the first autoimmune disease where the diagnosis is based on a serological test?

• Is a blood test a solid enough foundation upon which to build a lifetime of treatment for a patient?

• Should CD be the first autoimmune disease where the diagnosis is based on a serological test?on a serological test?

• Would you believe a single test if it were you?

on a serological test?

• Would you believe a single test if it were you?


October 2012 16

Histopathology of Celiac DiseaseHistopathology of Celiac Disease

1-21 2

4+


October 2012 17

Normal Intestine Celiac Disease

Gluten Sensitive EnteropathyGluten Sensitive EnteropathyII IIII IIIaIIIa IIIbIIIb IIIcIIIc

Few orno symptoms

Few orno symptoms

SymptomsSymptoms

•Little malabsorption

•No villous atrophy

•Little crypt hyperplasia

• increased IELs

•Little malabsorption

•No villous atrophy

•Little crypt hyperplasia

• increased IELs

•Minimal malabsorption

•Partial villous atrophy

•Some crypt hyperplasia

• Increased IELs

•Minimal malabsorption

•Partial villous atrophy

•Some crypt hyperplasia

• Increased IELs

•Extensive malabsorption

•Complete villous atrophy

•Marked crypt hyperplasia

• Increased IELs

•Extensive malabsorption

•Complete villous atrophy

•Marked crypt hyperplasia

• Increased IELs

CP1222653B-1


October 2012 18

Lymphocytic DuodenosisLymphocytic Duodenosis

• AKA Marsh 1• AKA Marsh 1

• >25 IELS/100 enterocytes

• Normal architecture

• 10-20 % are part of the spectrum of gluten sensitivity

Al NSAIDS H l i C h ’

• >25 IELS/100 enterocytes

• Normal architecture

• 10-20 % are part of the spectrum of gluten sensitivity

Al NSAIDS H l i C h ’• Also NSAIDS, H pylori, Crohn’s, Sjogren’s syndrome

• Also NSAIDS, H pylori, Crohn’s, Sjogren’s syndrome

Kakar et al. AJG, 2003VandeVoort et al. AJG 2009

Minimal histology and/or IBSMinimal histology and/or IBS--like symptomslike symptoms

TTG Ab positiveTTG Ab positive TTG Ab negativeTTG Ab negative

GFDGFD GenotypingGenotyping

HLA DQ2/8 +HLA DQ2/8 + HLA DQ2/8 HLA DQ2/8 --

Other causesOther causesGFDGFD

Consider rebiopsy 3Consider rebiopsy 3--6 months6 monthsAdapted from Verdu EF, et al. AJG 2009Adapted from Verdu EF, et al. AJG 2009

GFD trial? GFD trial?


October 2012 19

What About Patients on GFD Diet?

What About Patients on GFD Diet?

• Often unhappy patient• Often unhappy patient• Often unhappy patient

• Serology and biopsies can normalize

• HLA type might help

• Challenge

• Often unhappy patient

• Serology and biopsies can normalize

• HLA type might help

• Challenge• Challenge

• Some patients will not eat gluten

• Why argue with success if diet is nutritionally adequate?

• Challenge

• Some patients will not eat gluten

• Why argue with success if diet is nutritionally adequate?

Celiac Disease and HLA RiskCeliac Disease and HLA Risk

General

Celiac diseaseCeliac diseaseGeneralpopulation

DQ2 or DQ8HLA DQB1*02/DQA*05(DQ2)or DQB1*0302/DQA1*03 (DQ8)

HLA DQB1*02/DQA*05(DQ2)or DQB1*0302/DQA1*03 (DQ8)

DQ2 or DQ8


October 2012 20

When to Use HLA?When to Use HLA?

• People on a gluten free diet ( including refractory)

S ti iti bi ti t

• People on a gluten free diet ( including refractory)

S ti iti bi ti t• Seronegative positive biopsy patients

• Those at genetic risk who are seronegative• Down’s Syndrome

• Turner’s syndrome

• William’s syndrome

• Seronegative positive biopsy patients

• Those at genetic risk who are seronegative• Down’s Syndrome

• Turner’s syndrome

• William’s syndromeUsual prevalence of DQ2

• Asymptomatic family members

• Type one diabetes

• Asymptomatic family members

• Type one diabetesHigh prevalence of DQ2/8

Endoscopic Features of Celiac Disease

Endoscopic Features of Celiac Disease

Is it necessary to biopsy the normal looking duodenum?Is it necessary to biopsy the normal looking duodenum?


October 2012 21

Celiac Disease for the Endoscopist

Celiac Disease for the Endoscopist

• Common in the people getting EGDs• Common in the people getting EGDs• Common in the people getting EGDs• 2-3% of dyspepsia

• 5-7 % of type one diabetes

• 5-8% of iron deficiency anemia

• 2-5% of osteoporosis

• 5% of diarrhea predominant IBS

• 5%-8% of PBC/ autoimmune hepatitis

• Common in the people getting EGDs• 2-3% of dyspepsia

• 5-7 % of type one diabetes

• 5-8% of iron deficiency anemia

• 2-5% of osteoporosis

• 5% of diarrhea predominant IBS

• 5%-8% of PBC/ autoimmune hepatitisp

• 6% of recurrent pancreatitis ( papillary stenosis)

• 5-10% of family members

• Expect cases of CD /50 endoscopies

• No biopsies = no diagnosis!

p

• 6% of recurrent pancreatitis ( papillary stenosis)

• 5-10% of family members

• Expect cases of CD /50 endoscopies

• No biopsies = no diagnosis!

Macroscopic Clues to Microscopic Changes

•Loss of folds with inflationinflation•Fissuring/Scalloping•Mosaic pattern

•Nodularity


October 2012 22

Fissuring on FoldsFissuring on Folds

SENSITIVITY OF ENDOSCOPIC MARKERS

SENSITIVITY OF ENDOSCOPIC MARKERS

• Sensitivity 50 60%• Sensitivity 50 60%• Sensitivity ~ 50-60%

• Specificity >90%

• Loss of folds-most sensitive (Oxentenko,AJG, 2002)

• Markers less sensitive with PVA

52% Vs 82%

• Sensitivity ~ 50-60%

• Specificity >90%

• Loss of folds-most sensitive (Oxentenko,AJG, 2002)

• Markers less sensitive with PVA

52% Vs 82%52% Vs. 82% (Dickey, AJG, 2001)

• Non atrophic celiac disease (maki, et al, gastro 2008)

• If you want to find CD: biopsy it!

52% Vs. 82% (Dickey, AJG, 2001)

• Non atrophic celiac disease (maki, et al, gastro 2008)

• If you want to find CD: biopsy it!


October 2012 23

Endoscopic Features of Atrophy

Endoscopic Features of Atrophy

• Capsule better • Capsule better psensitivity(92%) than endoscopy (~50%)

• Markers of atrophy• Fissure

• Scalloping

psensitivity(92%) than endoscopy (~50%)

• Markers of atrophy• Fissure

• Scalloping• Scalloping

• Mosaic pattern

• Loss of villi

• Scalloping

• Mosaic pattern

• Loss of villi

Culliford A, et al. Gastrointest Endosc 2005;62: 55

Petriotene R, et al. Am J Gastroenterol 2005; 100: 685

Murray , Rubio-Tapia, et al. CGH, 2007

Celiac Disease Management 2012?

Celiac Disease Management 2012?

• Symptomatic patient• Symptomatic patient• Symptomatic patient

• Primary doctor finds Sero+

• Referred for biopsy

• Follow up from GI doc

• Symptomatic patient

• Primary doctor finds Sero+

• Referred for biopsy

• Follow up from GI doc


October 2012 24

Management Plan Management Plan

• Explain the disease• Explain the disease• Explain the disease

• Strongly advocate a gluten free diet

• Refer to expert dietitian!

• Check bone density

• Identify and treat deficiencies

• 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

• Support group

• Calcium and vitamin D replacement

• Support group

TreatmentTreatment

• Only treatment for celiac disease is a gluten-free diet (GFD)• Strict, lifelong diet

• Only treatment for celiac disease is a gluten-free diet (GFD)• Strict, lifelong diet

• Avoid:• Wheat

• Rye

• Barley

• Avoid:• Wheat

• Rye

• Barley


October 2012 25

ChallengesChallenges• Social occasions

• Isolation

B i diff t ( t )

• Social occasions

• Isolation

B i diff t ( t )• Being different ( teenagers)

• Family support

• Community support

• Depression/anxiety

• Being different ( teenagers)

• Family support

• Community support

• Depression/anxiety

“I can resist anything except temptation” Oscar Wilde

“I can resist anything except temptation” Oscar Wilde

Follow Up Of Celiac DiseaseFollow Up Of Celiac Disease

• Symptoms resolve in 1-3 months• 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 year

• Serology level fall substantially in 6 months

• Biopsies improve more slowly in adults than children

• Re biopsy in 1 year• Re-biopsy in 1 year

• Dietitian follow up for compliance

• MD interest is crucial

• Re-biopsy in 1 year

• Dietitian follow up for compliance

• MD interest is crucial


October 2012 26

Dangers of Non-Compliance

Dangers of Non-Compliance

• Increased mortality H l t l 1989• Increased mortality H l t l 1989• Increased mortality Holmes et al. 1989 Corrao et al.

• Osteoporosis Cellier

• Lymphoma Holmes et al.

• Other cancers Green, 2006

• Increased mortality Holmes et al. 1989 Corrao et al.

• Osteoporosis Cellier

• Lymphoma Holmes et al.

• Other cancers Green, 2006

• Psychological effects hallert• Psychological effects hallert

Histologic Healing in AdultsHistologic Healing in Adults

Author Countr “n” % TimeAuthor Country

n % healing

Time on GFD

Grefte J1 Holland 22 0% 2 years

Bardella M2

Italy 114 17.5% 2 years

Rubio-T i *

USA 241 34% 2 yearsTapia* 66% 5 years

Ciacci C3 Italy 390 44% 7 years

Tursi A4 Italy 42 59.5% 2 years

Collin P5 Finland 65 96% 8 years1 J Clin Pathol 1988; 2 Histopathology 2007; 3Digestion 2002; 4Endoscopy 2006; 5Gastrointest Endosc 2004

* Rubio-Tapia A, et al. Am J Gastro 2010


October 2012 27

Non Responsive Celiac DiseaseNon Responsive Celiac Disease

• Primary: no initial response to gluten free diet

• Primary: no initial response to gluten free dietdiet

• Secondary: relapse following initial response

• 17% of celiacs at a support group had diarrhea1

18 7% f f l t l ti 2

diet

• Secondary: relapse following initial response

• 17% of celiacs at a support group had diarrhea1

18 7% f f l t l ti 2• 18.7% of a referral center population2

• 9.9% of primary patients

• 35% of referral patients

• 18.7% of a referral center population2

• 9.9% of primary patients

• 35% of referral patients

1Fine et al. Gastro, 19972Leffler et al. CGH, 2007

Additional DiagnosesAdditional Diagnoses

gluten exposure

SIBO eating disorder

dissaccharidase def

refractory sprue

microscopic

IBS

microscopic colitis

Leffler et al. CGH 2007


October 2012 28

Refractory Celiac DiseaseRefractory Celiac Disease

• Very rare condition

• Symptomatic malabsorption

• Very rare condition

• Symptomatic malabsorption

• Severe enteropathy

• Lack of response to a GFD (exclusion diagnosis)

• 2 types

• Immune (Type 1): intraepithelial lymphocyte normal

• Clonal T-cell (Type 2): aberrant intraepithelial lymphocyte

• Severe enteropathy

• Lack of response to a GFD (exclusion diagnosis)

• 2 types

• Immune (Type 1): intraepithelial lymphocyte normal

• Clonal T-cell (Type 2): aberrant intraepithelial lymphocytelymphocyte

• But not overt lymphoma!

lymphocyte

• But not overt lymphoma!

Nutritional ManagementNutritional Management

• Protein calorie malnutrition• Protein calorie malnutrition• Protein calorie malnutrition• TPN

• Enteral elemental feeding

• Micronutrients• Iron, folate, B12

• Zinc and copper

• Protein calorie malnutrition• TPN

• Enteral elemental feeding

• Micronutrients• Iron, folate, B12

• Zinc and copper• Zinc and copper

• Bone disease • Vitamin D and calcium

• Parenteral antiresorptive agents

• Zinc and copper

• Bone disease • Vitamin D and calcium

• Parenteral antiresorptive agents


October 2012 29

Survival According SubtypeSurvival According Subtype

Gluten Free Diet Gluten Free Diet

Prevalence of Celiac Disease and Gluten Free Diet: NHANES 2009-2010

Celiac DiseaseCeliac Disease

Diagnosed CD

GFD without Dx of CD

Untreated CD

RubioRubio--Tapia, et al. AJG 2012 .Tapia, et al. AJG 2012 .

1.6 million 1.8 million1% of Caucasians


October 2012 30

Non-Celiac Gluten Sensitivity

The term NCGS relates to one or more of aThe 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 whomp p

CD has been excluded.

Ludvigsson JF, Leffler DA, Bai JC, et al. Gut (2012).

• Gluten-sensitive diarrhea without celiac disease first described as a clinical entity in 1980

• Gluten-sensitive diarrhea without celiac disease first described as a clinical entity in 1980

Gluten Sensitivity as a Clinical Entity

1980.• Females, chronic diarrhea, increased cellular

infiltration of lamina propria• 3-month gluten-free diet (GFD)• HLA DQ2 associated with celiac disease

Chronic Diarrhea patients with HLA DQ2

1980.• Females, chronic diarrhea, increased cellular

infiltration of lamina propria• 3-month gluten-free diet (GFD)• HLA DQ2 associated with celiac disease

Chronic Diarrhea patients with HLA DQ2• Chronic Diarrhea patients with HLA-DQ2 expression profit from a gluten-free diet

• Chronic Diarrhea patients with HLA-DQ2 expression profit from a gluten-free diet

Cooper BT, et al. Gastro, 1980.

Howell MD, et al. J Exp Med, 1986.

(Wahnschaffe, Gastroenterology, 2001)


October 2012 31

HLA-DQ2 positive IBS patients had markers ( IELS or gliadin sIgA )HLA-DQ2 positive IBS patients had markers ( IELS or gliadin sIgA )

• Cohort of 102 IBS patients, 35% (n=36),

• Cohort of 102 IBS patients, 35% (n=36),

100

Increased AspirateGliadin or TTG IgA

Increased IEL

HLA DQ2 +HLA DQ2 +

were HLA DQ2+

• All were TTG IgA -

• 36% of HLA + IBS patients had ↑ IEL’s

• 58% had + IgA gliadin or TTG in aspirate.

were HLA DQ2+

• All were TTG IgA -

• 36% of HLA + IBS patients had ↑ IEL’s

• 58% had + IgA gliadin or TTG in aspirate. 40

60

80

100

op

ort

ion

of

pat

ien

ts, %

HLA DQ2 HLA DQ2 --

o G asp ateo G asp ate

Wahnschaffe U, et al. Gastro, 2001.

0

20P

ro

Normalization of GI symptom score and stool frequency achieved with GFD

••N=41 IBSN=41 IBS--DD

••66--month GFDmonth GFD

••GI symptoms and GI symptoms and stool frequencystool frequency

••HLA DQ2 status and HLA DQ2 status and IgG TTG/AGA may IgG TTG/AGA may predict clinical predict clinical response to a GFDresponse to a GFD

Wahnschaffe U, et al. CGH, 2007.

••Histology does not Histology does not predict responsepredict response

••TTG IgG, GS marker?TTG IgG, GS marker?


October 2012 32

Gluten Sensitivity as a clinical entity: “Celiac-Lite”

Genetic susceptibilityGenetic susceptibility

HLA DQ2/DQ8HLA DQ2/DQ8

Loss of gluten toleranceLoss of gluten tolerance

Gluten Sensitivity:Gluten Sensitivity:Celiac disease:Celiac disease: yy

↑ IEL +↑ IEL +

Serum TTG Ab Serum TTG Ab --

No mucosal atrophyNo mucosal atrophy

Response to GFDResponse to GFD

Celiac disease:Celiac disease:

Serum TTG Ab + Serum TTG Ab +

Mucosal atrophy +Mucosal atrophy + ?precursor

Condition of morphological, immunological, or functional disorder that responds to

gluten exclusion in the absence of celiac di

Condition of morphological, immunological, or functional disorder that responds to

gluten exclusion in the absence of celiac di

Gluten Sensitivity Celiac Lite”

disease.

• Gluten sensitive diarrhea

• Immunopathological changes in the SB mucosa

• ↑ Intraepithelial lymphocytes (IEL)

disease.

• Gluten sensitive diarrhea

• Immunopathological changes in the SB mucosa

• ↑ Intraepithelial lymphocytes (IEL)

• ↑ IgA deposits intestinal villi

• ↑ Secreted Ab against gliadin

• HLA predicted

• ↑ IgA deposits intestinal villi

• ↑ Secreted Ab against gliadin

• HLA predictedAdapted from Verdu EF, et al. AJG, 2009.


October 2012 33

Gluten Sensitive GI Symptoms“Celiac Like”

Gluten Sensitive GI Symptoms“Celiac Like”

• Self identified gluten sensitivity

• Gi Symptoms

• Self identified gluten sensitivity

• Gi Symptomsy p

• Challenge study• Randomized • Double blind placebo controlled

• Effect not HLA dependent• Highly select group

y p

• Challenge study• Randomized • Double blind placebo controlled

• Effect not HLA dependent• Highly select group• Highly select group• Highly select group

“Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial”.Biesiekierski JR et al. AJG 2011

Are there other potential mechanism of gluten in symptoms in IBS?

Are there other potential mechanism of gluten in symptoms in IBS?


October 2012 34

Gluten

Stress pathways Receptors pathways

α gliadin p31-43

Multiple immune effects of gluten

LGQQQPFPPQQPY QQQQQQQQQQQQILQQILQQQVLQQSTYQLLQELCCAHLW

CXCR3 MIC IL-15

α gliadin p31-43

Tryptic digested gliadin

EGFR pMAPKMyD88

FQQPQQQYPSSQ SQQPYLQLQ

? HLA-E

HLA-E

TLR-4 ?

Increased intestinal permeability

APC activationInflammatory cytokines

Epithelial activationUpregulation of IL-15 and EGFRUpregulation of stress-induced MHC-Ib

APC maturationInflammatory cytokines IFN-α

HLA-E surface expressionand stabilization

IL-15?IFN−α?

Altered Permeability and Mucosal Immune gene expression in Non-Celiac

Gluten Sensitivity

Altered Permeability and Mucosal Immune gene expression in Non-Celiac

Gluten Sensitivity

• Decreased IP in GS• Increased expression of claudin 4• Reduced Fox p3• Increased TLR2• Comparison group Dyspepsia• 5 hour urinary excretion of LA/MA

• Decreased IP in GS• Increased expression of claudin 4• Reduced Fox p3• Increased TLR2• Comparison group Dyspepsia• 5 hour urinary excretion of LA/MA• 5 hour urinary excretion of LA/MA• LA/MA is affected by transit

• Transit may be affected HLA

• 5 hour urinary excretion of LA/MA• LA/MA is affected by transit

• Transit may be affected HLASapone et al, BMC Medicine, 2011Vazquez-Roque, AJP , in press


October 2012 35

Gluten Intolerance/Sensitivity

Enteropathy-CD4 anti-gluten T cells- TG2

Dermatitis(Dermatitis herpetiformis)

IBSOther(neuropathy)Ataxia

- epithelial “stress”- IL-15- IFN-α- other- activated IE-CTL

- CD4 anti-gluten T cells Tg6- other? ?

- anti-TG2 antibodies AGA(immune complexes)

- epithelial “stress”- epithelial IL-15

Genetic backgroundEnvironmental factors

Adapted from JabriAdapted from Jabri

Potential CD CD

Epithelial distress

Extraintestinal inflammation

Gluten sensitivity may have a spectrum of effects

Anti-glutenT and B cell response

Extraintestinal inflammation?

Mucosalinflammation

with and withoutExtraintestinal manifestation

- Autoimmunity (T1D)- Latent innate response

to gluten

Epithelial DistressAnti-gluten T cell response


+/orAnti-TG2


+Anti-TG2

IBSGluten-dependent

Extraintestinalmanifestation

with villous atrophy

Gantibodies

Gantibodies

+Epithelial distress

Adaptive antiAdaptive anti-gluten immunityTG2 activation?


October 2012 36

The Spectrum of Altered Responses to Gluten Beyond Celiac Disease

Genetic susceptibility

celiac disease

PotentialMarsh 0-I

Dermatitis Anemia

Latent

Gluten celiac diseaseMarsh III-IVMarsh I&II

References:Salmi 2006; Paparo 2005; Kurppa 2009; Vande Voort 2009; Walker 2010; Verdu 2009

Dermatitis herpetiformis

AnemiaInfertilityNeurologicalDisease associations

sensitiveIBSMarsh I

Glutensensitive

Enteropathy-CD4 anti-gluten T cells

TG2

Dermatitis(Dermatitis herpetiformis)

IBSOther(neuropathy)

- TG2- epithelial “stress”- IL-15- IFN-α- other- activated IE-CTL

- CD4 anti-gluten T cells ?- other?

- anti-TG2 antibodies ? (immune complexes)

- epithelial “stress”- epithelial IL-15

Genetic backgroundEnvironmental factors


October 2012 37

ChallengesChallenges

••Clear define each syndrome and casesClear define each syndrome and cases••Prove gluten dependenceProve gluten dependence

••DeDe--challengechallenge••ReRe--challengechallenge

••Double blind Placebo controlledDouble blind Placebo controlled••Duration?Duration?••Safety in neurological syndromeSafety in neurological syndrome

D fi h i ( )D fi h i ( )••Define mechanism(s)Define mechanism(s)••Detection/diagnosisDetection/diagnosis

Challenge: How Can We Detect NCGS?

Challenge: How Can We Detect NCGS?

••Most patients have to find Most patients have to find themselves despite us!themselves despite us!themselves despite us! themselves despite us! ••Self treatment is not Self treatment is not satisfactorysatisfactory••Missed disease Missed disease


October 2012 38

Challenge: DiagnosisChallenge: Diagnosis

••Diagnosis:Diagnosis:••Rule out celiac disease/ other diseaseRule out celiac disease/ other disease••Role of antibodies: Role of antibodies:

••secreted/ serum/deposits secreted/ serum/deposits ••AntiAnti--gliadin gliadin

••specific for NCGI ( need good specific for NCGI ( need good controls) IBS for GS IBScontrols) IBS for GS IBSAb t l i l tiAb t l i l ti••Ab to luminal antigens Ab to luminal antigens

(dietary/microbes)(dietary/microbes)••Intestinal permeability*Intestinal permeability*••HLA prediction “celiacHLA prediction “celiac--Lite”Lite”

Evidence Frequently Lacking for Non Coeliac Gluten Intolerance

Evidence Frequently Lacking for Non Coeliac Gluten Intolerance

• Prospective studies• Adequate and appropriate controls

• Gluten sensitive IBS versus IBS

• Prospective studies• Adequate and appropriate controls

• Gluten sensitive IBS versus IBS

• Gluten dependence (DB RCT)*• De-challenge• Challenge

• Proven Gluten Exclusivity• Other parts of wheat

Other foods/ dietary factors

• Gluten dependence (DB RCT)*• De-challenge• Challenge

• Proven Gluten Exclusivity• Other parts of wheat

Other foods/ dietary factors• Other foods/ dietary factors• Confounding problems common in

functional disease

• Other foods/ dietary factors• Confounding problems common in

functional disease

Carraccio et al. December issue of AJG


October 2012 39

SummarySummary

• Celiac Disease is common ~1%

• It can present in many ways or remain covert

• Celiac Disease is common ~1%

• It can present in many ways or remain covert• It can present in many ways or remain covert

• Frequent in the endoscopy suite

• Detected by serology ( tTg-IgA) biopsy

• Requires a gluten free diet

• Refractory sprue is a rare but serious issue

• A lot of people eat gluten free

• It can present in many ways or remain covert

• Frequent in the endoscopy suite

• Detected by serology ( tTg-IgA) biopsy

• Requires a gluten free diet

• Refractory sprue is a rare but serious issue

• A lot of people eat gluten freep p g

• Non-celiac gluten sensitivity is real but unclear in frequency, etiology

• Management of NCGS is still gluten avoidance to avoid symptoms

p p g

• Non-celiac gluten sensitivity is real but unclear in frequency, etiology

• Management of NCGS is still gluten avoidance to avoid symptoms

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