Diagnostic Criteria of celiac disease

Dr. Virendra Kumar GuptaMD Pediatrics,MIAP

Fellowship In pediatric Gastroentero-Hepatology & Liver Transplantation

Assistant Professor Institute of Paediatric Gastroenterology

Nims University Jaipur

DEFINITION

• An immune-mediated systemic disorder• Elicited by gluten and related prolamines• In genetically (mainly HLA) susceptible individuals• Characterized by a combination of:

gluten dependent clinical manifestations anti-tissue transglutaminase (TG2) antibodies enteropathy

Husby et al. JPGN 2012

CLINICAL SPECTRUM• Symptomatic CD

– Frank clinical features

• Silent CD

– No symptoms but +ve serology and HPE.

– In most cases identified by serologic screening in at-risk groups

• Latent CD

– Normal HPE but before or after have shown Gluten dependent enteropathy

• Potential CD

– Normal HPE but Positive serology .

– It might or might not be symptomaticESPGHAN Guidelines for Diagnosis of Coeliac Disease

PREVALENCE IN CHILDREN BETWEEN 2.5 AND 15 YEARS OF AGE:

3 to 13 per 1000 children or

approximately 1 in 300 to 1 in 80 children

CDHNF/NASPGHAN guidelines on the Diagnosis and Treatment of Celiac Disease in Children JPGN ©2005;

Volume 40, Number 1 (Jan): pages1-19.

Increased prevalence of CD in children with

• Type 1 diabetes 2–12 %• Autoimmune liver disease 12-13 %• Autoimmune thyroid disease up to 7 %• IgA deficiency 2-8 %• Down’s syndrome 5-12 %• Turner syndrome 2-5 %• Williams’ syndrome up to 9 %• First degree relatives with CD 10-20 %

Garampazzi A, Rapa A, Mura S, et al. Clinical pattern of celiac diseaseis still changing. J Pediatr Gastroenterol Nutr 2007;45:611–4.

Prevalent, But Under Diagnosed

– Those not diagnosed have a higher death rate– Raise awareness

IMPROVE SCREENING

Celiac disease as a multiorgan autoimmune diseaseGeneral:

Puberty & growth delay

MalignanciesAnemia

GI system:Diarrhea, vomiting

Distension, painMalnutrition, weight lossHepatitis,

cholangitis

Bone:Osteoporosis,

fracturesArthritis

Dental anomalies

Skin & mucosa:Dermatitis

herpetiformisAphtous

stomatitisHair loss

Heart:Carditis

CNS:Ataxia, seizures

Depression

Reproductive system:

MiscarriageInfertility

EVIDENCE-BASEDGUIDELINES FOR CD DIAGNOSIS

• AHRQ (USA, 2004) Adults and children

Rostom A, et al.. Celiac Disease. EvidenceReport/ Technology AssessmentNo. 104. AHRQ Publication No. 04-E029-2, 2004

• NICE guidelines (UK, 2009)Adults and childrenFor GP’s and general paediatricians

NICE Clinical Guidelines 86. Coeliac Disease: Recognition and assessment of coeliac disease. UK, May 2009

Guidelines: AHRQ (USA, 2004)

Main issues1. Sensitivity/specificity of

serological tests2. Prevalence / incidence

of CD3. CD associated lymphoma4. Consequences of testing

for CD5. Interventions for

adherence to a gluten freediet

Conclusions1. Sensitivity and specificity

of EMA and TG2 are quitehigh

2. CD common, prevalencein the general populationlikely close to 1:100

3. Education/participation incoeliac societies improvescompliance with a GFD

Rostom A, et al.. Celiac Disease. Evidence Report/Technology Assessment No. 104.AHRQ Publication No. 04 E029 2, 2004‐ ‐

Who Should Be Tested for CD?Group 1:unexplained symptoms and signs chronic or intermittent diarrhoea,failure to thrive, weight loss,stunted growth, delayed puberty,amenorrhoea, iron-deficiencyanaemia, nausea or vomiting,chronic abdominal pain, crampingor distension, chronicconstipation, chronic fatigue,recurrent aphthous stomatitis(mouth ulcers), dermatitisherpetiformis–like rash, fracture With inadequatetraumas/osteopenia/osteoporosi, and abnormal liver biochemistry.

Group 2:Asymptomatic increased risk

for CD Type 1 diabetes mellitus

(T1DM)Autoimmune thyroid diseaseAutoimmune liver diseaseIgA deficiencyDown syndromeTurner syndromeWilliams syndrome First-degree relatives

DIAGNOSTIC TOOLS

• CD-specific Antibody Tests

• Histological Analysis of Duodenal Biopsies

• HLA Testing for HLA-DQ2 and HLA-DQ8

ANTIBODIES

• Anti-tTG /TG2 (tissue transglutaminase)

• Anti-EMA (Endomysial antibody)

• Anti- DGP ( deamidated Gliadin Peptides)

– IgA level should be done with EMA/tTG

• Anti- Gliadin/Anti- Reticulin

SENSITIVITY/SPECIFICITYTest % Sensitivity % Specificity Age

tTG-IgA 90-100 94-100 Children

84-100 91-100 Combined

EMA-IgA 87-95 95-100 Adults

  88-100 90-100 Children

  91-98 99-100 Combined

DGP 91 98 Combined

Am J Gastroenterol. 2009 Jan;104(1):154-63.

False Positive tTG/ Serology– Other autoimmune conditions

– Infections

– Tumors

– Tissue damage

FALSE NEGATIVE SEROLOGY (tTG)

• Children younger than 2 yr

• Restricted gluten consumption

• Severe symptoms

• On immunosuppressive medications

• Technical problems

HISTOPATHOLOGY

• Crypt Hyperplasia

• Crypt to villous ratio is increased

• Intra-Epithelial Lymphocytosis

• Abnormal surface epithelium

• Subtotal to total villous atrophy

ENDOSCOPY & BIOPSY

Biopsies should be taken preferably during

upper endoscopy

bulb (at least 1 biopsy)

second or third portion of duodenum (at least 4

biopsies)

19

Normal small bowel Celiac disease

Gluten

Gluten-free diet

MARSH Staging

Causes of Flat Mucosa (Villous Atrophy)

• Celiac Disease

• Giardiasis

• HIV Enteropathy

• PEM

• CMPI

• Bacterial Overgrowth

• Primary immunodeficiency

• Tropical sprue

• Chemotherapy & irradiation

• Eosinophilic Gastroenteritis

• Multiple genes involved• The most consistent genetic component

depends on the presence of HLA-DQ (DQ2 and/or DQ8) genes

• One or both of these genes are found in 95% of celiac patients

• Having one or more of these genes doesn’t mean you will develop celiac, but if you have the disease you likely have the gene.

HLA

?? ?

?

Gluten

Celiac Disease

+

Genes

Genetics

22

HLA TYPING• HLA DQ2 and DQ8

– Strong negative predictive value

– Present in > 95 % patients of CD

– Present in > 30% normal population

– Weak positive predictive value

• Diagnosis without biopsy is still not recommended in India

& Developing countries

• Reliable HLA testing and EMA estimation is not widely

available

• Secondly tTG is being done by various labs with different

kits and their standardization is doubtful, so >10 times

criteria is also difficult to implement.

Anti TG2 & total IgA*‐

Anti TG2‐positive

Anti TG2‐negative

Paed. GI discusses with family the 2 diagnostic pathways and consequences considering patient’s history & anti TG2 titers‐

Consider further diagnostic testing if:IgA deficientAge: < 2 yearsHistory: low gluten intake‐

‐ drug pretreatment-severe symptoms-associated diseases

Positive Anti‐TG2

> 10 x normal

EMA & HLA testing for DQ2/DQ8

Positive Anti‐TG2<10 xnormal

OEGD & biopsiesNot

available

Not CD

EMA+vHLA +v

EMA+vHLA -v

EMA-vHLA -v

EMA-vHLA +v

Marsh 0 1‐ Marsh 2 or 3

CD+

GFD& F/u

Consider false neg. HLA testConsider biopsies

Consider false pos. Anti TG2‐

Unclear caseConsider:

false pos. serologyfalse neg. biopsy or

potential CDExtended evaluation ofHLA/serology/biopsies

GFD& F/u

CD+

Child / Adolescent with Symptoms suggestive of CD

*or specific IgG based tests

HLA DQ testing (+/ Anti TG2)‐ ‐

Consider retesting in intervals orif symptomatic

HLA positive forDQ2 and/or DQ8

Anti TG2 & total IgA*‐

EMA

Not CD,no risk

Positive Anti TG2‐> 3x normal

Marsh 2 or 3

CD+

GFD& F/u

Consider:Transient / false pos.

anti TG2‐F/u on normal diet with

further serological testing

Consider: age, false neg. results,

exclude IgA deficiency and history

of low gluten intake or drugs

Asymptomatic Person at Genetic Risk for CDExplain implication of positive test result(s) and get consent for testing

HLA negative forDQ2 and/or DQ8

Anti TG2 negative‐Positive Anti TG2‐< 3x normal

Not CD

EMA negativeEMA positive

OEGD & biopsies:1 x bulbus & 4 x parsdescendens, properhistological work up

Unclear caseF/u on normal dietConsider: false pos.serology, false neg.

biopsy or potential CD

Marsh 0- 1‐

*or specific IgG based tests

CELIAC DISEASE

Gluten Free DietNutritional Education

Dietician

Periodic assessment of Symptoms, Diet & Serology

SerologyAbnormal

?

Reinforce adherence

Symptoms Present ?

Evaluate for other causes of symptoms

Consider Re- Biopsy

FOLLOW UP

Yes No

Yes

No

GLUTEN CHALLENGE- When and How ?

• Performed under special circumstances- Doubt exists about the initial • Gluten challenge should be discouraged

Before a child is 5 years old

During the pubertal growth spurt• Gluten challenge always should be performed

Under strict medical supervision

Preferably by a paediatric gastroenterologist

Preceded by HLA testing /assessment of duodenal histology

Ensuring that a normal amount of gluten in the diet is ingested

IgA anti-tTg antibody should be measured during the challenge period

Challenge for practical purposes is considered-Complete after 2 years

Follow-up should be continued -relapse may occur at a later time.

Why different algorithms for symptomatic andasymptomatic (at risk) patients?

1. False positive or transient TG2 antibody levels more frequent in genetically at risk persons than symptomatic cases

2. TG2 titres with normal histology (Marsh 0) are often of low titre (<3 x upper limit of normal)

3. In asymptomatic patients with low antibody levels there no urgency to perform biopsies compared to symptomatic patients with the same low levels.

Treatment

• GLUTEN FREE DIET (dietician consult)

• Identification and treatment of nutritional deficiencies• Pneumococcal vaccine

“A New Hope For CD Sufferers?”• New study, no conclusions yet• Pills that break down gluten• Immunotherapy: training the immune system

to tolerate gluten through injections

+ ?

CONCLUSION• CD is common • IgA tTG -good screening test for CD. ( exceptions

< 2 years)• A gluten-free diet (GFD) should be introduced

only after the completion of the diagnostic process, when a conclusive diagnosis has been made( expensive and lifelong diet ).

THANKS