Celiac Disease and malabsorption

Malabsorption and
celiac disease
Dr. Yasmin Köller, Mucosal Immunology group
Department klinische Forschung, Bern
2. February 2016
[email protected]
Celiac disease
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Signs and symptoms
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Definition and epidemiology
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Cause and risk factors
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Pathophysiology
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Diagnosis
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Treatment
Definition and epidemiology
Definition
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Malabsorption represents the pathological
interference with the normal physiological
sequence of digestion (intraluminal process),
absorption (mucosal process) and transport
(postmucosal events) of nutrients.
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Celiac disease - Autoimmune disease that is
characterised by the malabsorption of gluten in the
small intestine in genetically predisposed
individuals.
Epidemiology
Abadie V, Sollid LM, Barreiro LB, Jabri B. Integration of genetic and immunological insights into a model of celiac disease pathogenesis.
Annu Rev Immunol 2011;29:493–525.
๏ Affects ~1% of the general population
๏ Men > Women
๏ Ingested gluten, infant feeding patterns, the spectrum of intestinal infections,
gut microbiota colonisation
Celiac Disease Epidemiological
Study in USA
Population screened
13145
Healthy Individuals
4126
Risk Groups
9019
Symptomatic subjects
3236
Positive
31
Negative
4095
Prevalence
1:133
Positive
81
Negative
3155
Prevalence
1:40
1st degree relatives
4508
Positive
205
Negative
4303
Prevalence
1:22
2nd degree relatives
1275
Positive
33
Negative
1242
Prevalence
1:39
Projected number of celiacs in the U.S.A.: 2,115,954
Actual number of known celiacs in the U.S.A.: 40,000
For each known celiac there are 53 undiagnosed patients.
A. Fasano et al., Arch Int Med 2003;163:286-292.
• 85% of affected people are undiagnosed
Signs and symptoms
Symptoms
Symptoms in children
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abdominal bloating and pain
chronic diarrhea
vomiting
constipation
pale, foul-smelling, or fatty stool
weight loss
fatigue
irritability and behavioural issues
dental enamel defects of the permanent
teeth
delayed growth and puberty
short stature
failure to thrive
Attention Deficit Hyperactivity Disorder
(ADHD)
Symptoms in adults
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unexplained iron-deficiency anemia
fatigue
bone or joint pain
arthritis
bone loss or osteoporosis
depression or anxiety
tingling numbness in the hands and feet
seizures or migraines
missed menstrual periods
infertility or recurrent miscarriage
canker sores inside the mouth
an itchy skin rash called dermatitis
herpetiformis
Bloating,
abdominal pain
oral ulcera
Symptoms
Dermatitis
herpitiformis
dental enamel defects
Symptoms
Malabsorption-related symptoms
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Carbohydrates: Weight loss, fatigue, lack of energy
Iron: Iron-deficiency anemia
Vitamin B12: Megaloblastic anemia
Calcium/Vitamin D: Osteopenia and osteoporosis
Vitamin K deficiency: Abnormal coagulation, bleeding
Causes and risk factors
What is gluten/gliadin?
• Broad term for various proteins, called prolamin(e)s
• Each grain has its own specific prolamin – Wheat: gliadin
plant storage proteins with a high
proline and glutamine content
Genetic predisposition to develop
celiac disease
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95% of people with celiac disease have the HLADQ variant DQ2 or DQ8 (DQ2 > DQ8)
Number of HLA Alleles June 2007
MHC class I
HLA-A
HLA-B
HLA-C
574 (24)
920 (49)
311 (9)
HLA-E
HLA-F
HLA-G
9
21
28
HLA-DRA
HLA-DRB
HLA-DQA1
HLA-DQB1
HLA-DPA1
HLA-DPB1
3
583 (20)
34
86 (7)
23
127
HLA-DMA
HLA-DMB
HLA-DOA
HLA-DOB
4
7
12
9
MICA
MICB
TAP1
TAP2
61
30
7
4
MHC class II
Tight binding of DQ2 and DQ8 to gliadin peptides
Genetics
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Several genes are involved
The most consistent genetic component
depends on the presence of HLA-DQ
(DQ2 and / or DQ8) genes
Other genes (not yet identified) account for 60
% of the inherited component of the disease
HLA-DQ2 and / or DQ8 genes are necessary
(No DQ2/8, no Celiac Disease!) but not
sufficient for the development of the disease
Genes
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?
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HLA
+
Gluten
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Associated
Disorders/Symptoms
10%
8%
6%
4%
2%
0%
Pathophysiology
Pathogenesis
Genetics
Gluten
Necessary
Causes
Gender
Infant feeding
Infections
Others
Pathogenesis
?
Risk Factors
Celiac disease
Modellvorstellung der Interaktionen zwischen Protein-Prozessierung und spezifischen Immunreaktionen im Darm bei Zoeliakie. Gluten
wird aus der Nahrung durch Verdauungsenzyme (z.B. Prolin-Endopeptidasen) in stabile Peptide gespalten (mit Prolin-reichen PQPQLPY
Motiven) Die Peptide werden absorbiert und in die Lamina propria transportiert, wo sie durch eine Transglutaminase (tTG2, tissue
transglutaminase-2) modifiziert werden und in Assoziation mit HLA-DQ2 oder -DQ8 Molekülen auf Antigen-praesentierenden Zellen an
CD4 T Zellen praesentiert werden. Diese aktivierten T Zellen produzieren Interferonγ und weitere entzündungsfördernde Zytokine, welche
die charakteristischen Veränderungen (z.B. Villus - Atrophie, Kryptenhyperplasie) vermitteln
Tissue transglutaminase (tTG)
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catalyses transamination or deamination
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gluten peptides are a preferential substrate
3x
Thiol residue in the
active site
Thioester
lysine residue
of tTG
production of autoantibodies against
tTG anti-transglutaminase antibodies
(ATA)
cross-linked isopeptide
—> new epitopes,
immunogenic
e.g. Glutamic acid
e.g. glutamine
hydrolysation
Diagnosis
Tests for Celiac Disease
• Serology
• Duodenal biopsy
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HLA typing
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Video capsule endoscopy
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Fecal testing
Serological Tests
• Anti-gliadin antibodies (AGA)
• Anti-endomysial antibodies (EMA)
• Anti-tissue transglutaminase antibodies
(TTG)
• Anti-deamidated gliadin antibodies
Serological Test Comparison
Sensitivity
(+ with CD)
Specificity
(- w/o CD)
Cost
AGA IgG
69-85%
73-90%
$
AGA IgA
75-90%
82-95%
$
EMA IgA
88-99%
90-100%
$$$
TTG IgA
90-100%
94-100%
$$
Caveats
• IgA deficiency
– anti-TTG IgG or deamidated gliadin peptide IgG
– consider QUIGs if failure to thrive, diarrhea
• <2 years of age
– consider deamidated gliadin IgA + IgG if other serologies
negative
HLA Tests
HLA alleles associated with Celiac Disease
• DQ2 found in 95% of celiac patients
• DQ8 found in remaining patients
• DQ2 found in ~30% of general population
• DQ8 found in ~10% of general population
Value of HLA testing
• High negative predictive value
– Negativity for DQ2/DQ8 excludes diagnosis of
Celiac Disease with 99% confidence
Schuppan. Gastroenterology 2000;119:234
Kaukinen. Am J Gastroenterol 2002;97:695
HLA Typing
• Having DQ2 or DQ8 does not mean you
have disease
• Having DQ2 or DQ8 means that you are
part of the 40% of the world that may one
day develop celiac (and a host of other
diseases)
Biopsy
• Endoscopy and duodenal biopsy
– Spectrum of endoscopic findings
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Normal
Scalloping of duodenal folds
Mucosal fissures
Nodularity
– Spectrum of histologic findings
Histological Features
Normal 0
Infiltrative 1
Partial atrophy 3a
Subtotal atrophy 3b
Hyperplastic 2
Total atrophy 3c
Horvath K. Recent Advances in Pediatrics, 2002.
Histology
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Villous atrophy
Villous blunting
Increased intraepithelial lymphocytes
Crypt hyperplasia
Vilus atrophy
Crypt hyperplasia
mucosal inflammation
Treatment
Treatment
• Only treatment for
celiac disease is a
gluten-free diet (GFD)
– Strict, lifelong diet
– Avoid:
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Wheat
Rye
Barley
Contaminated oats
Sources of Gluten
• OBVIOUS SOURCES
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Bread
Bagels
Cakes
Cereal
Cookies
Pasta / noodles
Pastries / pies
Rolls
Sources of Gluten
• Not so obvious sources
A note on oats
• What about oats?
– Avenin does not provoke an autoimmune
response
– Many sources of commercial oats are
cross-contaminated with gluten grains
– OTC medications, including MVI
– Hydrolyzed vegetable protein
– Hydrolyzed plant protein
– Soy sauce, imitation pepper, malt
– Graham, bulgur, farina, spelt
– Malted beverages, beer, ale, lager
So what does that leave?
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Rice, corn, arrowroot, potato and nut flour
Buckwheat, flax, sorghum, tapioca, millet
Eggs, lentils, peas, beans, nuts, tofu
Meat, fish, poultry
Fruit, vegetables
Popcorn, ice cream, corn chips, chocolate
Wine, cider, distilled alcoholic beverages
Glutenfrei
Glutenhaltig
Getreide
Mais, Reis, Wildreis (ist ein Blumensamen), Buchweizen,
Hirse, Amaranth, Johannisbrotkernmehl, Quinoa
Weizen, Roggen, Hafer (siehe oben), Gerste, Dinkel, Spelt, Triticale,
Emmer, Einkorn, Kamut, Grünkern, Bulgur, Couscous
Kartoffelprodukte
Kartoffeln, Süßkartoffeln
Achtung bei Pommes frittes! Oft mit Gluten kontaminiert! Auch
Vorsicht bei Chips und anderen Snacks
Gemüse
alle Gemüsesorten in frischer, gefrorener oder
getrockneter Form.
auch verträglich: Tapioka, Maniok, Bohnen, Erbsen,
Linsen, Sojabohnen, Eßkastanien (Maroni), ...
Gemüse in Dosen oder in Fertigprodukten ist dann unverträglich,
wenn bestimmte Emulgatoren, Konservierungsstoffe,
Verdickungsmittel, Stabilisatoren oder Stärke enthalten sind!
"Nüsse"
Haselnüsse, Walnüsse, Mandeln, Cashewnüsse,
Paranüsse, Erdnüsse, Sonnenblumenkerne, Sesam, Mohn,
Leinsamen, Kokosnuß
geröstete Nüsse oder Erdnüsse mit Geschmack - Zutatenliste
beachten!
Obst
alle frischen, gefrorenen und getrockneten Obstsorten
Achtung: Fruchtfüllungen enthalten oft Verdickungsmittel und
Stärke; Dörrobst wird oft "gemehlt"; Vorsicht auch bei Sprossen und
Keimlingen (da sind oft Getreidesorten dabei!)
Eier
alle Teile des Eis
Milchprodukte
Milch, Topfen (Quark), Naturjoghurt, Sahne, Hartkäse, Kefir,
Dickmilch, Molke
Einige Käsesorten enthalten Verdickungsmittel! Manchmal wird
glutenhaltige Stärke zugesetzt (vor allem bei geraspeltem Käse!)
Zutatenliste beachten!
Fleisch
alle Arten von Fleisch, Geflügel und Wild, gekochter und
roher Schinken
Wurstwaren sind oft nicht glutenfrei! Zutatenliste beachten!
Fisch und Meeresfrüchte
Frischer Fisch
Fischerzeugnisse, Fischkonserven, panierter Fisch, Rollmöpse, ...
Fette, Öle und Gewürze
Pflanzenöle, Butter, Margarine, Schmalz, Essig, reine
Gewürze, Salz, Pfeffer und alle frischen Kräuter
Margarine und pflanzliche Öle müssen auf Zusätze hin überprüft
werden; Vorsicht bei bereits verwendetem Frittierfett
(Glutenrückstände); Bechamel Sauce
Getränke
Früchtetee, Kräutertee, Säfte, frisch gebrühter Kaffee,
Wein, Sekt, Cola und Limonaden (Zutatenliste beachten!),
Weinbrand, Rum, klare Schnäpse
andere Lebensmittel
Honig, Zucker, Tofu (ohne Zusätze), Sojamilch (Zutatenliste
beachten!)
löslicher Kaffee (je nach Marke), Getreidekaffee,
Kaffeefertiggetränke (z.B. Automaten-Kaffee, Kakao),
Kakaofertiggetränke, Bier, Malzgetränke, Maltwhiskey, isotonische
Getränke
Seitan (ist praktisch reines Gluten!)
Questions?