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Pediatrics Grand Rounds 7 October 2011

Univeristy of Texas Health Science Center at San Antonio

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GLUTEN SENSITIVE

ENTEROPATHY ADVANCES & CLINICAL IMPLICATIONS BEYOND

THE GUT

Ruba Abdelhadi, M.D.

Objectives

Recent advances

Pathogenesis

Manifestations

Complications

Treatment

Silly Yak !

Coeliac, / ’siːli.æk /

Greek κοιλιακός

/ koiliakόs /abdominal

Aretaeus of Cappadocia

Pathophysiology

Autoimmune disorder

Genetic susceptibility

HLA DR3 (DR5/DR7) or HLA DR4

Environmental trigger

Other agents

Infection

Epidemiology

Prevalence

Small intestinal biopsy → incidence to 1:500

Serologic tests → anti-endomysial antibodies

Europe → 1:130 to 1:300

US → prevalence 1:133

Fasano et al. Arch Intern Med. 2003

Ethnicity → 5% prevalence in Saharawi population

Catassi et al. Lancet. 1999

Pathophysiology

Autoimmune disorder

Abnormal permeability

“Missing peptidase”?

Loosening intestinal tight junctions

↑ permeability to macromolecules

Zonulin induces tight junction disassembly

↑ Zonulin expression in small intestine

http://en.wikipedia.org/wiki/Wikipedia:IPA_for_English


http://en.wikipedia.org/wiki/Greek_language




http://en.wikipedia.org/wiki/Aretaeus_of_Cappadocia



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Pathophysiology cont.

Innate Immune system

T-cell mediated

In situ T-cell recognition of dominant gliadin epitopes

> 50 epitopes

Dominant -gliadin T-cell epitope, single tTG-modified peptide

Maiuri et al. Lancet. 2003


↑ HLA-DR expression on epithelium & lamina propria macrophages

↑ ICAM-1 overexpression

Intraepithelial CD8+ T lymphocyte invasion

95% DR3 (or DR5/DR7 heterozygous) genotype DQ2 ,-heterodimer

DQA1*0501/ DQB1*0201

5% DR4 DQ8 ,-heterodimer

DQA1*0301/DQB1*0302

CD4+ DQ2 & DQ8 molecules on surface of APCs

Bind peptides to be presented to CD4+ T cells


Autoantobodies

Antiendomysial ab

Antireticulin ab

Autoantigen- tTG

GLN → deamidation → GLU

↑ DQ binding & T cell recognition


Gluten digested → gliadin

↑ Intestinal permeability

tTG interaction

Peptide deamidation

↑ Affinity for HLA-DQ2/ DQ8 heterodimer

Release IL-2, IL-5

Anti-tGA abs

↓ TGF activation

Marsh MN. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity ('celiac sprue'). Gastroenterology 1992; 102: 330–354.

Morphology Morphology

Maiuri et al, FAS engagement drives apoptosis of enterocytes of coeliac

patients. Gut 2001; 48: 418–424.

Maiuri et al, Interleukin 15 mediates epithelial changes in celiac disease.

Gastroenterology 2000; 119: 996–1006.



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Clinical Presentation

Typical

Atypical

Silent

Latent

Gastrointestinal

Extra-intestinal

Asymptomatic

Oligosymptomatic


Typical Diarrhea

Vomiting

Failure to thrive

Anorexia

Constipation

Recurrent abdominal pain

Distension

Muscle wasting

Malnutrition

Behavioral changes

„Celiac crisis‟


Atypical Atypical or extra-intestinal

Minimal GI symptoms/signs

Absent GI symptoms/signs

Fatigue

Malaise

Anemia

'Atypical' or 'Extraintestinal' Celiac

Dermatitis herpetiformis

Permanent enamel hypoplasia

Resistant iron-deficient anemia

Short stature

Delayed puberty

Chronic hepatitis & hypertransaminasemia

Primary biliary cirrhosis

Arthritis

Osteopenia/osteoporosis

Epilepsy/occipital calcifications

Primary ataxia, white-matter focal lesions

Psychiatric disorders

Infertility of women


Silent No signs or symptoms

Gluten-dependent duodenal

mucosal changes


Latent No signs or symptoms

Duodenal mucosa normal

Gluten-dependent changes with

or without symptoms to appear

later in time



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•Latent, silent, oligosymptomatic

•Symptomatic, celiac disease

Guandalini, Gastroenterology, 2002

Presentation varies with age

Arthritis & Arthralgia

Arthritis including those on GFD

Lubrano et al. Br J Rheumatol. 1996

2-3% of children with juvenile chronic arthritis

Lepore et al. J Pediatr. 1996

Dental enamel hypoplasia

Dental enamel defects

Minimal gastrointestinal

symptoms

Up To Date, Courtesy of Lisa Papagiannoulis, DDS, MS,

School of Dental Medicine, University of Athens, Greece

Short stature & Delayed puberty

Short stature may be the only manifestation

8–10% of children with 'idiopathic' short stature

Tumer et al. Pediatr Int. 2001

Delayed onset of menarche

Smecuol et al. Eur J Gastroenterol Hepatol. 1996

Chronic Hepatitis

Hypertransaminasemia

Chronic hepatitis

Hypertransaminasemia

Non-specific reactive hepatitis

Severe liver disease- hepatic failure

GFD may reverse liver failure

Kaukinen K et al. Gastroenterology. 2002



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Neurological problems

Idiopathic cerebellar ataxia

Hadjivassiliou et al Brain 2003

Occipital calcifications

Intractable epilepsy

Gobbi et al Lancet 1992

Focal brain white-matter lesions

Seizures, hypotonia, ataxia

Kieslich et al. Pediatrics 2001


Autism, no evidence !

ADHD, no evidence !


Depression

Anxiety

Osteopenia & Osteoporosis

Low bone mineral density

Oteoporosis

Increased incidence of fractures

Screen all Celiac patients?

Osteoporosis

↓ absorption of calcium a/o vitamin D

Autoimmune aggression of bone matrix

Sugai E et al. J Clin Immunol. 2002

Iron-deficiency anemia

Resistant to oral iron supplementation

5% of patients with anemia

Prevalence ↑ 8.5% in microcytic anemia

Corazza et al. Scand J Gastroenterol. 1995

Screening adult patients w folate or iron deficiency

11% positive

Howard MR et al. J Clin Pathol. 2002


Variant of celiac disease

Blistering skin rash

Elbows, knees, buttocks

Dermal granular IgA deposits

Rash & mucosal morphology

improve on GFD

Infertility

Unexplained ♀ infertility

8.9 X relative abortion risk

Ciacci et al Am J Gastroenterol 1996

Fetuses of celiac mothers

Fetuses of celiac fathers !

Lower birth weight

Prematurity

Ludvigsson et al. Gut. 2001



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Diagnosis- ESPGHAN 1970 Diagnosis- ESPGHAN 1990

ESPGHAN, new diagnostic criteria Characteristic changes of the duodenal mucosa

Signs and/or symptoms consistent with celiac

Full & unequivocal clinical remission after withdrawal of gluten

Disappearance of circulating antibodies

Italian multicenter investigation

>3000 children

Guandalini S et al, Diagnosis of coeliac disease: time for a change? Arch Dis

Child. 1989

Diagnosis-Endoscopy

Absent mucosal Folds Reduced mucosal folds

http://www.celiacdiseasecenter.columbia.edu/C_Doctors/C06-pEndoscopy.htm

Diagnosis-Endoscopy

Scaloping Cracking


Diagnosis-Endoscopy

Mosaic pattern Mucosal fissures


Diagnosis-Biopsies, How many?

At least four !

Pais WP et al. How many duodenal biopsy specimens are required to make a

diagnosis of celiac disease . Gastrointest Endosc 2008

Only 2 biopsy specimens

→ confirmed diagnosis in 90%

→ suspected diagnosis in all

For 100% confidence in diagnosis, 4 duodenal biopsy

specimens should be taken



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Diagnosis-Pathology

Normal villious architecture blunting and flattening of villi

http://library.med.utah.edu/WebPath/GIHTML/GI152.html

↑ chronic inflammation Loss of crypts ↑ mitotic activity Loss of brush border Infiltration with lymphocytes & plasma cells

http://library.med.utah.edu/WebPath/GIHTML/GI152.html

Diagnosis-Pathology

http://www.pathology.vcu.edu/education/gi/lab2.c.html

Intraepithelial Lymphocytes

CD8+ T lymphocytes γ d receptors

→ Typical

→ Not pathognomonic

→ Early, subtle sign

↔ concordant serology

↔ clinical findings

Δ surface/ volume ratio

Diagnosis-Histology vs Serology

Normal histology and “false” positive serology??

Collin P et al. Scand J Gastroenterol 1993

Niveloni S et al. Am J Gastroenterol 2000

Serology → morphological Δ

Follow up EMA, tTGA

Repeat endoscopy

Diagnosis-Serology

AGA-IgG 85-98% sensitivity

↓ specificity

value in monitoring

AGA-IgA 95-100% specificity

↓ sensitivity

value in monitoring

EMA

tTG-IgA

EMA-IgG1

value in IgA def

tTG-IgG

value in IgA def

Quantitative total IgA

IgA deficiency in 3% of celiac patients

Diagnosis-EMA

Immunofluorescence on exposure to serum Monkey esophageal

Human umbilical cord smooth muscle

Subjective operator assessment

↑ specificity (93.9–99.9%)

↑ sensitivity (82.7–92.5%) Stern M. J Pediatr Gastroenterol Nutr 2000

Good inter-lab reliability

Expensive

Limited screening



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Diagnosis-tTG

Dieterich W et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nature Med 1997

ELISA, guineapig IgA tTG ab

98.1% sensitive

94.7% specific

Dieterich W et al. Autoantibodies to tissue transglutaminase as predictors of celiac disease. Gastroenterology 1998

Human antigen ↔ guinea pig antigen

Gold standard?

EMA versus human tTG ab

EMA semiquantitative, observer-dependent, costly, time-consuming

Still, tTG ab < specific than EMA ab

Risk Stratification- Prometheus

Category Number

DQ Genotype Category Increased Risk Over General Population1,2

Relative Risk

8 DQ2 Homozygous 31X EXTREMELY HIGH

7 DQ2/other high risk gene 16X VERY HIGH

6 DQ2/DQ8 14X VERY HIGH

5 DQ8 Homozygous 10X HIGH

4 DQ2 heterozygous 10X HIGH

3 DQ8 heterozygous 2X MODERATE

2 DQ2/other low risk gene <1X LOW

1 DQ2-, DQ8- <0.1X EXTREMELY LOW

Pietzak M, Schofield T. Gastroenterology. 2007;132:2585-2587.

Fasano A, et al. Arch Intern Med. 2003;163:286-292.

Koning F. Gastroenterology. 2005;129:1294–1301.

Risk Stratification- Clinical Benefits

↓ Psychological burden of disease risk in families

↓ Number of at-risk individuals needing serial antibody testing

Aids in the interpretation of serologic results

Pre-test probability of disease

Provides sufficient diagnostic confidence in certain clinical situations

Proceed to gluten-free diet without small-bowel biopsy ??

Provides assistance in diagnosing a patient already on a gluten-free diet or

with an equivocal biopsy result

Liu E, et al. Gastroenterology. 2005;128(suppl 1):S33-S37.

Associated conditions with ↑ prevalence

of celiac disease

Insulin-dependent diabetes mellitus

Thyroiditis

Sjögren's syndrome & other CTDs


Down's syndrome

Williams' syndrome

Turner's syndrome

First-degree relatives of celiac patients

6%

4%

5%

3%

12%

6%

6%

8–10%

Associated autoimmune conditions with ↑

prevalence of celiac disease

Autoimmune myocarditis

Frustaci A et al. t al. Circulation 2002

Insulin-dependent diabetes mellitus

Thyroiditis

Alopecia

Ventura A et al. Study Group for Autoimmune Disorders in Celiac Disease. Gastroenterology 1999

Sjögren's syndrome & other CTDs


Type 1 Diabetes- IDDM

Small intestinal biopsy in a diabetic 8% with typical features of celiac disease on duodenal biopsy

„Real‟ % higher by serial screening

The diagnosis of IDDM precedes that of celiac by years in 90%

Should an asymptomatic diabetic be on GFD?

If found positive at screening: controversial

No convincing evidence that GFD has obvious effect on diabetes

GFD improves glycemic control & GI symptoms

GFD prevents osteopenia, infertility, malignancy



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Down's syndrome

5-12 % prevalence

Majority have GI symptoms Bonamico M et al. J Pediatr Gastroenterol Nutr 2001

Still, 30% may be asymptomatic

Fe def anemia, ↓ Ca, stunted height & weight

Recommend screening for celiac disease GFD if positive

Rescreen or CeliapLus genetic testing for HLA haplotypes

Screening in Williams' syndrome ↑ incidence of celiac disease

Complications

Hyposplenism

Non-responsive celiac disease

Refractory sprue

Malignancy


Enamel hypoplasia

Anemia

Short stature

Delayed puberty

Chronic hepatitis

Arthritis

Osteopenia

Osteoporosis

Epilepsy


Infertility of women

Complications- Hyposplenism

Splenic atrophy

30-50% affected

Arterial hypotension in 70%

Older patients

Howell–Jolly bodies

Thrombocytosis

Confirmed by imaging techniques.

Complications- Refractory Sprue

„Non-responsive‟ celiac disease on GFD

Celiac-like enteropathy?

True refractory sprue?

Crohn‟s?

Concomitant food allergy

Cow‟s milk protein allergy

Transient disaccharidase def

“Adult-type„, 'late-onset' lactase deficiency

Apparently Non-responsive Celiac

disease- „Refractory Sprue'

Continued ingestion of gluten

Incorrect diagnosis

Crohn's disease

Autoimmune enteropathy

Eosinophilic gastroenteritis

Giardiasis

Irritable bowel syndrome

Pancreatic insufficiency

Complications- Refractory Sprue

Multicenter study in France, Cellier C et al. French Coeliac Disease Study

Group. Lancet 2000

Abnormal monoclonal intraepithelial T lymphocytes expressing CD3c

Lacks CD3 & CD8 surface expression

T cell receptor- gene rearrangements

Aberrant clonal population of intraepithelial lymphocytes

Cryptic enteropathy-associated T-cell lymphoma

Immunohistochemical technique for rapid identification

Patey-Mariaud De Serre et al. Histopathology 2000

Aggressive immunosuppressive regimens

Cyclosporine, infliximab



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Complications- Malignancy

Flat mucosa Pleomorphism

Treatment

Total lifelong GFD, wheat barley rye

What about oats? Genetically oats are entirely unrelated

Vader LW et al. J Exp Med 2002

Uncontrolled harvesting & milling procedures

Cross-contamination of oats w gluten

Lactose?

Milk protein allergy?

Threshold, 'zero tolerance„

Ruba Abdelhadi, M.D.

Thank You!