Update Zoeliakie in der Inneren Medizin. Andrew Macpherson Director of Gastroenterology Inselspital Bern

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1 Update Zoeliakie in der Inneren Medizin Andrew Macpherson Director of Gastroenterology Inselspital Bern

2 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)

3 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

4 Jeder sollte an die Möglichkeit einer Zoeliakie denken Group Prevalence Asymptomatic 1 in 133 individuals GI symptoms 1 in 56 First-degree relative 1 in 22 with celiac disease Second-degree relative 1 in 39 with celiac disease 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:

5 Prävalenz der Zoeliakie im Rahmen Group anderer Erkrankungen Iron-deficiency anaemia 3-5% Elevated liver transaminases 2-9% Unexplained infertility 2-4% Down s syndrome 5% Autoimmune thyroid disease 2-7% T1 diabetes 2-5% Osteoporosis 1-4% Prevalence Rostom A, et al. GASTROENTEROLOGY 2006;131:

6 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:

7 Der Zoeliakie-Eisberg 3% (US) 30% (Finland) diagnosed 70% - 97% undiagnosed

8 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

9 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

10 Warum ist die sichere Diagnose so Retrospective cohort study from Sweden Duodenal/jejunal Bx (from 28 Pathology departments) 1. Villous atrophy (Marsh 3) N= Enteropathy (Marsh 1 or 2) N= Latent celiac disease N=3719 wichtig? 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 after year 1 Marsh 1 or Marsh Latent celiac disease Excess mortality rate/1000 patient years Ludvigsson et al., Small intestinal histopathology and mortality risk in celiac disease JAMA 2009, 302,

11 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 Gluten ataxia TG7,8 Not defined Factor XIII Plasma Coagulation stabilisation

12 Wie Antikörper gegen Gewebetransglutaminasen entstehen

13 Wie Antikörper gegen Gewebetransglutaminasen entstehen

14 Test Wie gut sind unsere diagnostischen Sensitivity (Range) Tests? Specificity (Range) Positive predictive value IgA AGA 85 (57-100) 90 (47-94) IgG AGA 84 (42-100) 80 (50-94) EMA 95 (86-100) 99 (97-100) IgA anti- TG IgG anti- TG 98 (78-100) 98 (90-100) (45-95) 95 (94-100) Negative predictive value Leffler DA & Schuppan D Am J Gastroenterol 2010;105:

15 Was bedeutet positiver prädiktiver Wert? Test result Patient has disease Patient does not have disease Positive True positive (TP) False positive (FP) Positive predictive value = TP / (TP + FP) Negative False negative (FN) True negative (TN) Negative predictive value = TN / (TN + FN) Sensitivity = TP / (TP+FN) Specificity = TN / (TN +FP)

16 Was bedeutet positiver prädiktiver Wert? Test result Patient has disease Patient does not have disease Positive True positive (TP) False positive (FP) Positive predictive value = TP / (TP + FP) Positive predictive value of 83% = 17/100 patients incorrectly committed to lifelong gluten-free diet without biopsy evidence

17 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

18 Celiac disease Lymphoma/ulcerative jejunoileitis Infective - Giardia etc. Eosinophilic enteritis Tropical sprue Common variable disease GVHD Milk protein intolerance Collagenous sprue AIDS enteropathy

19 Same patient 4 months after gluten-free diet Celiac disease

20 Patient A

21 O.U (Patient A) stained for CD8 alpha Iron deficient, antiendomysial IgA positive

22 Control CD8 alpha stain

23 Wer glaubt, die Therapie sei banal hat nie eine glutenfreie Diät ausprobiert! Gluten is everywhere

24 Wer glaubt, die Therapie sei banal hat nie eine glutenfreie Diät ausprobiert! Breading Broth/Bouillon Candy Drink mixes Communion wafers Croutons Malt on cereals Marinades Pasta Play-Doh Processed meats Sauces Pet food Dressing Flour Gravies Imitation bacon Imitation seafood Lipstick/lip balm Seasoning Self basting poultry Soup bases Thickeners Toothpaste Medications

25 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 Patients under-report gluten intake, but antibodies are even more insensitive in follow-up

26 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!!!

27 Problemfelder Dietary indiscretion Mistaken gluten intake (cosmetics/medications) 2 o 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

28 Ebenfalls zu berücksichtigen: FBC, LFTs, U&Es, TFTs, Glucose, Urine Folate, B12, B6, ferritin Serum IgG, IgM, IgA CRP Anti-thyroid, ANA, RhF