Celiac disease update for internal medicine

Update Zoeliakie
in der Inneren
Medizin
Andrew Macpherson
Director of Gastroenterology
Inselspital Bern
Bisherige und teils fehlerhafte
Vorstellungen
• Celiac disease diagnosis is relatively
straightforward with small intestinal biopsy or
serology
• Mainly confined to the intestine
• Not dangerous apart from a risk of lymphoma
• Easy treatment with gluten-free diet
• About 1/1000 of population (Talley et al. Am.
J. Gastroenterol. 1994)
Sie werden feststellen…
• Celiac disease is extremely common and we are
diagnosing only about 10% of the cases in our
community
• Undiagnosed patients are dying, and not just
from lymphoma
• That it is a multisystem disorder
• The reliability of the antibody tests – can they be
used in follow-up?
• Do you still need a intestinal biopsy for diagnosis?
• That treatment with diet is NOT EASY
Jeder sollte an die Möglichkeit einer
Zoeliakie denken
Group
Asymptomatic
individuals
GI symptoms
First-degree relative
with celiac disease
Second-degree relative
with celiac disease
Prevalence
1 in 133
1 in 56
1 in 22
1 in 39
Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of celiac disease in at-risk and not-at-risk groups in the United States: a
large multicenter study. Arch Intern Med. 2003;163: 286-292
Prävalenz der Zoeliakie im Rahmen
anderer Erkrankungen
Group
Prevalence
Iron-deficiency anaemia
Elevated liver transaminases
Unexplained infertility
Down’s syndrome
Autoimmune thyroid disease
T1 diabetes
Osteoporosis
3-5%
2-9%
2-4%
5%
2-7%
2-5%
1-4%
Rostom A, et al. GASTROENTEROLOGY 2006;131:1981–2002
Wie gut sind wir in der Diagnostik?
• Population-based study of 1612 patients
with celiac disease
• Diarrhoea most common symptom >85%
• Average duration of symptoms prior to
diagnosis = 11 years
• >30% of patients had consulted 2 or more
gastroenterologists prior to diagnosis
Green PHR , Stavropoulos SN, Panagi SG, et al. Characteristics of adult celiac disease in the USA: results of a national survey. Am J
Gastroenterol. 2001;96:126-131
Der „Zoeliakie-Eisberg“
3% (US) – 30% (Finland)
diagnosed
70% - 97%
undiagnosed
Und es kommt noch schlimmer!
3% (US) – 30% (Finland) diagnosed
c75% of patients taking a
gluten-free diet DO NOT
HAVE CELIAC DISEASE
70% - 97% undiagnosed
Wie sich Zoeliakie 2011 präsentiert
Presents at any age to any specialty
The great underdiagnosed condition of our age
Clinical malabsorption
Weight loss or low BMI
Asymptomatic
Anaemia
Fe deficiency
LFT elevations
Constipation
Diarrhoea
Apthous ulcers
Nausea/vomiting
Heartburn
Patients with
„IBS, lactose
intolerance,
brittle
diabetes“
Etc., etc........
Fatigue
Infertility
Headaches
Arthralgias
Myalgias
Alopecia
Dental defects
Cognitive issues
Pancreatitis
Warum ist die sichere Diagnose so
wichtig?
Retrospective cohort study
from Sweden
Duodenal/jejunal Bx (from 28 Pathology
departments)
1. Villous atrophy (Marsh 3) N= 29’096
2. Enteropathy (Marsh 1 or 2) N=13’306
3. Latent celiac disease N=3719
Using Swedish Total Population Register,
risk of death through August 31, 2008
estimated, compared with age- and sexmatched controls from the general
population
Biopsy result
Death ratio
in year 1
Death ratio Excess mortality
after year 1 rate/1000 patient
years
Marsh 1 or 2
Marsh 3
4.6
2.8
1.4
1.3
10.8
2.9
„Latent celiac
disease“
1.8
1.3
1.7
Ludvigsson et al., Small intestinal histopathology and mortality risk in celiac disease JAMA 2009, 302, 1171-1178
Die Gruppe der
Gewebstransglutaminasen
Class
Location
Clinical relevance
TG1
Keratinocytes
Congenital
ichthyosis
TG2 (tissue
trnasglutaminase)
GI, kidney, lung,
RBC, WBC, smooth
muscle,
endothelium
Celiac disease,
diabetic
nephropathy, cystic
fibrosis
TG3,5
Skin
Dermatitis
herpetiformis
TG4
Prostate
TG6
Brain
TG7,8
Not defined
Factor XIII
Plasma
Gluten ataxia
Coagulation
stabilisation
Wie Antikörper gegen
Gewebetransglutaminasen entstehen
Wie Antikörper gegen
Gewebetransglutaminasen entstehen
Wie gut sind unsere diagnostischen
Tests ?
Test
Sensitivity
(Range)
Specificity
(Range)
Positive
predictive
value
18
IgA AGA
85 (57-100) 90 (47-94)
IgG AGA
EMA
IgA antiTG
IgG antiTG
84 (42-100) 80 (50-94) 31
95 (86-100) 99 (97-100) 83
98 (78-100) 98 (90-100) 72
99
99
99
70 (45-95)
99
95 (94-100) 42
Leffler DA & Schuppan D Am J Gastroenterol 2010;105:2520–2524
Negative
predictive
value
99
Was bedeutet
„positiver prädiktiver Wert“ ?
Test result
Patient has
disease
Patient does
not have
disease
Positive
True positive
(TP)
False
negative
(FN)
Sensitivity =
TP / (TP+FN)
False
positive (FP)
True
negative
(TN)
Specificity =
TN / (TN
+FP)
Negative
Positive predictive
value = TP / (TP + FP)
Negative predictive
value = TN / (TN + FN)
Was bedeutet
„positiver prädiktiver Wert“ ?
Test result
Patient has
disease
Patient does
not have
disease
Positive
True positive False
Positive predictive
(TP)
positive (FP) value = TP / (TP + FP)
Positive predictive value of 83% = 17/100
patients incorrectly committed to lifelong gluten-free diet without biopsy
evidence
Keine DIAGNOSE ohne BIOPSIE
A) Upper small intestinal biopsy with subtotal villous atrophy that improves
on GFD*
B) Partial villous atrophy with true transverse orientation that improves on
GFD*
C) Intestinal lymphocytosis (Marsh I) or hyperplastic crypts (Marsh
II)associated with positive EMA or anti-TG in DQ2 or DQ8 patient with
improvement on GFD*
* Improvement can be either 1. clinical with resolution of positive antibodies
or 2. histological without antibodies in DQ2/DQ8 positive patients
• DQ2/DQ8 negative patients, those with terminal ileal villous atrophy and
antibody negative patients are unlikely to have celiac disease
∆∆
Celiac disease
Lymphoma/ulcerative jejunoileitis
Infective - Giardia etc.
Eosinophilic enteritis
Tropical sprue
Common variable disease
GVHD
Milk protein intolerance
Collagenous sprue
AIDS enteropathy
Same patient 4 months
after gluten-free diet
∆ Celiac disease
Patient A
O.U. 24.4.59. (Patient A) stained for CD8 alpha
Iron deficient, antiendomysial IgA positive
Control CD8 alpha stain
Wer glaubt, die Therapie sei banal hat
nie eine glutenfreie Diät ausprobiert !
Gluten is
everywhere
Wer glaubt, die Therapie sei banal hat
nie eine glutenfreie Diät ausprobiert !
Breading
Broth/Bouillon
Candy
Drink mixes
Communion wafers
Croutons
Malt on cereals
Dressing
Flour
Gravies
Imitation bacon
Imitation seafood
Lipstick/lip balm
Marinades
Pasta
Play-Doh
Processed meats
Sauces
Pet food
Seasoning
Self basting poultry
Soup bases
Thickeners
Toothpaste
Medications
Follow-up: Professionelle Ernährungsberatung
und HÄNGT NICHT AN DEN ANTIKÖRPERN
Clinical assessment scale (1-6)
1—Excellent: Gluten < x3/year (n = 68)
2—Good: Gluten =1/month (n = 53)
3—Fair: Gluten = x2-3/month (n = 19)
4—Poor: Gluten = x2 week (n = 7)
5—Very Poor: Gluten > x2/week(n = 5)
6—Not on GFD(n = 2)
Leffler et al., Aliment.Pharm.Ther. 2007 1227-1235
Patients under-report
gluten intake, but
antibodies are even
more insensitive in
follow-up
Wieviel Gluten ist zuviel ?
• WHO defines naturally gluten free foods as
<20PPM gluten and foods processed to
become gluten-free as <200PPM
• 200PPM = approximate intake of 60mg
gluten/day
• Sensitivity to gluten is variable, but 10mg/day
can be enough to damage the mucosa
Es braucht professionelle Ernährungsberatung:
die Diät ist nicht für alle gleich !!!
Problemfelder
• Dietary indiscretion
• Mistaken gluten intake (cosmetics/medications)
• 2o Lactase or sucrase-isomaltase deficiency (should
be formally tested not trial by diet –far too
restrictive)
• Constipation (consequence of diet)
• Overgrowth
• Bile acid malabsorption
• Development of ulcerative jejunoileitis or
lymphoma
Ebenfalls zu berücksichtigen:
•
•
•
•
•
FBC, LFTs, U&Es, TFTs, Glucose, Urine
Folate, B12, B6, ferritin
Serum IgG, IgM, IgA
CRP
Anti-thyroid, ANA, RhF