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Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
1
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
Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
2
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
Pathophysiology cont.
↑ 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
Pathophysiology cont.
Autoantobodies
Antiendomysial ab
Antireticulin ab
Autoantigen- tTG
GLN → deamidation → GLU
↑ DQ binding & T cell recognition
Pathophysiology cont.
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.
Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
3
Clinical Presentation
Typical
Atypical
Silent
Latent
Gastrointestinal
Extra-intestinal
Asymptomatic
Oligosymptomatic
Clinical Presentation
Typical Diarrhea
Vomiting
Failure to thrive
Anorexia
Constipation
Recurrent abdominal pain
Distension
Muscle wasting
Malnutrition
Behavioral changes
„Celiac crisis‟
Clinical Presentation
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
Clinical Presentation
Silent No signs or symptoms
Gluten-dependent duodenal
mucosal changes
Clinical Presentation
Latent No signs or symptoms
Duodenal mucosa normal
Gluten-dependent changes with
or without symptoms to appear
later in time
Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
4
•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
Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
5
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
Psychiatric disorders
Autism, no evidence !
ADHD, no evidence !
Psychiatric disorders
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
Dermatitis herpetiformis
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
Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
6
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
http://www.celiacdiseasecenter.columbia.edu/C_Doctors/C06-pEndoscopy.htm
Diagnosis-Endoscopy
Mosaic pattern Mucosal fissures
http://www.celiacdiseasecenter.columbia.edu/C_Doctors/C06-pEndoscopy.htm
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
Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
7
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
Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
8
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
Primary biliary cirrhosis
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
Primary biliary cirrhosis
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
Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
9
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
Dermatitis herpetiformis
Enamel hypoplasia
Anemia
Short stature
Delayed puberty
Chronic hepatitis
Arthritis
Osteopenia
Osteoporosis
Epilepsy
Psychiatric disorders
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
Pediatrics Grand Rounds 7 October 2011
Univeristy of Texas Health Science Center at San Antonio
10
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!