Celiac Disease and Gluten Sensitivity: New Tests and Approaches

Transcription

1 Celiac Disease and Gluten Sensitivity: New Tests and Approaches Joseph A Murray Mayo Clinic, Rochester, MN DISCLOSURE Relevant Financial Relationship(s) Alba Therapeutics: grant support Alvine Inc: Advisory Board Consultant: Ferring, Ironwood, Bayer, Flamentera, Arteille, Actiogenix, Shire, NexPep October

2 What is the connection between these? Introduction Celiac disease is well defined disease Non-Celiac Gluten sensitivity is not so well defined May share common o pathways ays to symptoms October

3 What is Celiac Disease? It is a inflammatory state of the small intestine that occurs in genetically predisposed individuals and resolves with exclusion of dietary gluten. Normal Celiac Disease Pathogenesis Genetics Gluten Necessary Causes Pathogenesis? Gender Infant feeding Infections* Others Risk Factors Celiac disease *Rotavirus at weaning Gastroenteritis in Adults Stene et al, AJG 2006 Riddle et al. AJG 2012 October

4 Presentations of Celiac Disease Classic malabsorptive syndrome( 25%) diarrhea, steatorrhea, weight loss, multiple deficiencies Monosymptomatic ( 50%) Anemia, diarrhea, lactose intolerance, constipation Acute Abdomen ( rare) abdominal pain, intussception, vomiting, obstruction perforation, lymphoma Non-GI presentations(25% ) Infertility, bone disease, neurological disease, short stature, brittle diabetes, chronic fatigue, abnormal LFTS Fe-Deficient Anemia Resistant to Oral Fe Most common non-gi manifestation in some studies Murray, CGH, % of adults with unexplained iron deficiency anemia have Celiac Disease 5-15% of patients undergoing endoscopy for fe deficiency anemia have celiac disease Vogelsang, 98; Grisolano, % of patients getting EGD for anemia do not get duodenal biopsies! Harewood, 2003 October

5 Celiac Disease: Acute Abdomen Mimic partial small bowel obstruction Perforation Stricture Lymphoma Intussusception Recurrent Pancreatitis 12/169 patients with recurrent idiopathic pancreatitis had celiac disease Papillary stenosis on manometry Pain responded to ERS and GFD Patel et al, GE Endoscopy, 1999 October

6 Abnormal Liver Blood Tests Incidental elevated serum transaminases (ALT, AST) Up to 9% may have silent Celiac Disease Liver biopsies in these patients showed non-specific reactive hepatitis Liver enzymes normalize on glutenfree diet Occasionally severe liver disease Rubio-Tapia et al. Liver international, 2008 RubioTapia and Murray, Hepatology, 2007 Who Gets Celiac Disease? Adults >> children, female > males Worldwide, mostly Caucasians Any age including elderly People with other immune disorders Type one diabetes mellitus Sjogren s syndrome Thyroid disease Lupus, Addison s disease Family members of celiacs October

7 How Common in the United States? The Prevalence of Celiac Disease in the United States Alberto Rubio-Tapia, Jonas F. Ludvigsson, Tricia L. Brantner, Joseph A. Murray, James E. Everhart Mayo Clinic and NIDDK* October

8 Assessment of Celiac Disease Status Direct Interview (two structured questions): Has a doctor or other health professional ever told you that you have celiac disease? Are you on a gluten-free diet? Serology testing: coded serum specimens shipped to celiac disease research laboratory at Mayo Clinic and tested between Jan 2009 and Jan 2011 Prevalence of Celiac Disease and Gluten Free Diet: NHANES Diagnosed CD Gluten Free Diet Celiac Disease GFD without Dx of CD 17% 83% Untreated CD 1.6 million 1.8 million 1% of Caucasians Rubio-Tapia, et al. AJG October

9 World Map Indicating Prevalence of Celiac Disease ~1% 1-2% >2% <0.5% Report of cases N/A Remes-Troche JM. Ramirez-Iglesias MT. Rubio-Tapia A. Alonso-Ramos A. Velazquez A. Uscanga LF. Journal of Clinical Gastroenterology. 40(8): , 2006 CP How Do You Find It? Diagnostic Tests October

10 Duration Of Symptoms Before Diagnosis Stoven et al. Poster, P154 ACG 2012 Detection versus Diagnosis Detecting CD is the not the same as confirming it! For detection you do not want to miss a case; maximize sensitivity For diagnosis you need confirmation: maximize specificity Traditionally serology first then biopsy October

11 Diagnostic Criteria Villous atrophy with chronic inflammation in the proximal small intestine while eating gluten* Objective clinical response to a gluten free diet Serology provides important supportive evidence ESPHGAN revised guidelines - Avoid Biopsy in some children? *IELS with Serology+ ESPHGAN Guidelines 1991 UEDW Guidelines 2001 AGA 2006 Comparison of Serological Tests Test Sens Spec Tech Cost HtTg Low $$ EMA High $$$$ Gliadin-IgA Low $ Gliadin-IgG Low $ October

12 Comparison of Serological Tests Test Sens Spec Tech Cost HtTg Low $$ EMA High $$$$ Gliadin-IgA Low $ Gliadin-IgG Low $ Deamidated Gliadin P Low $ Sensitivity of TTg-IGA October

13 Decrease in Sensitivity of ELISA Tests After Treatment with GFD Sensitivity 100 GCD ** ** ** ** GFD ** 42 8 ** 84 * *P<0.05 **P< AGA II IgA AGA II IgG AGA II IgA+G AGA IgA AGA IgG TTG IgA TTG IgG New ESPGHAN Guidelines Biopsy can be avoided if all of the following apply: ttg-iga > 10 x upper limit of normal Symptoms suggestive of celiac disease EMA+ (on a new blood sample) HLA = DQ2 or DQ8 Responds to gluten diet Highly Controversial! Husby et al, JPGN 2012 October

14 Can Serology Replace Biopsy? How Good is Serology in Practice Specificity of the tests TTg-IGA high >95% EMA-IGA high 76*-100% Variability: Lab to lab Kit to kit Reference ranges Performance * Mubarak et al, JPGN 2011 October

15 A Biopsy Is Not Always Necessary to Diagnose Celiac Disease Accuracy of High Titer Results Specificity (%) Sensitivity (%) PPV(%) NPV( %) EMA-IGA TTg-IGA > TTg-IgA > Issues: Retrospective study of real clinical practice Effect of serum testing prior to scope! Low accuracy of EMA Mubarak et al. JPGN., May Philosophy Is a blood test a solid enough foundation upon which to build a lifetime of treatment for a patient? Should CD be the first autoimmune disease where the diagnosis is based on a serological test? Would you believe a single test if it were you? October

16 Histopathology of Celiac Disease October

17 Normal Intestine Celiac Disease I Gluten Sensitive Enteropathy II IIIa IIIb IIIc Few or no symptoms Symptoms Little malabsorption No villous atrophy Little crypt hyperplasia increased IELs Minimal malabsorption Partial villous atrophy Some crypt hyperplasia Increased IELs Extensive malabsorption Complete villous atrophy Marked crypt hyperplasia Increased IELs CP B-1 October

18 Lymphocytic Duodenosis AKA Marsh 1 >25 IELS/100 enterocytes Normal architecture % are part of the spectrum of gluten sensitivity Also NSAIDS, H pylori, Crohn s, Sjogren s syndrome Kakar et al. AJG, 2003 VandeVoort et al. AJG 2009 Minimal histology and/or IBS-like symptoms TTG Ab positive TTG Ab negative GFD Genotyping HLA DQ2/8 + HLA DQ2/8 - GFD Other causes Adapted from Verdu EF, et al. AJG 2009 Consider rebiopsy 3-6 months GFD trial? October

19 What About Patients on GFD Diet? Often unhappy patient Serology and biopsies can normalize HLA type might help Challenge Some patients will not eat gluten Why argue with success if diet is nutritionally adequate? Celiac Disease and HLA Risk Celiac disease General population HLA DQB1*02/ DQA*05(DQ2) or DQB1*0302/ DQA1*03 (DQ8) DQ2 or DQ8 October

20 When to Use HLA? People on a gluten free diet ( including refractory) Seronegative positive biopsy patients t Those at genetic risk who are seronegative Down s Syndrome Turner s syndrome Usual prevalence of DQ2 William s syndrome Asymptomatic family members High prevalence Type one diabetes of DQ2/8 Endoscopic Features of Celiac Disease Is it necessary to biopsy the normal looking duodenum? October

21 Celiac Disease for the Endoscopist Common in the people getting EGDs 2-3% of dyspepsia 5-7 % of type one diabetes 5-8% of iron deficiency anemia 2-5% of osteoporosis 5% of diarrhea predominant IBS 5%-8% of PBC/ autoimmune hepatitis 6% of recurrent pancreatitis ( papillary stenosis) 5-10% of family members Expect cases of CD /50 endoscopies No biopsies = no diagnosis! Macroscopic Clues to Microscopic Changes Loss of folds with inflation Fissuring/Scalloping Mosaic pattern Nodularity October

22 Fissuring on Folds SENSITIVITY OF ENDOSCOPIC MARKERS Sensitivity ~ 50-60% Specificity >90% Loss of folds-most sensitive (Oxentenko,AJG, 2002) Markers less sensitive with PVA 52% Vs. 82% (Dickey, AJG, 2001) Non atrophic celiac disease (maki, et al, gastro 2008) If you want to find CD: biopsy it! October

23 Endoscopic Features of Atrophy Capsule better sensitivity(92%) than endoscopy (~50%) Markers of atrophy Fissure Scalloping Mosaic pattern Loss of villi Culliford A, et al. Gastrointest Endosc 2005;62: 55 Petriotene R, et al. Am J Gastroenterol 2005; 100: 685 Murray, Rubio-Tapia, et al. CGH, 2007 Celiac Disease Management 2012? Symptomatic patient Primary doctor finds Sero+ Referred for biopsy Follow up from GI doc October

24 Management Plan Explain the disease Strongly advocate a gluten free diet Refer to expert dietitian! Check bone density Identify and treat deficiencies Calcium and vitamin D replacement Support group Treatment Only treatment for celiac disease is a gluten-free diet (GFD) Strict, lifelong diet Avoid: Wheat Rye Barley October

25 Challenges Social occasions Isolation Being different ( teenagers) Family support Community support Depression/anxiety I can resist anything except temptation Oscar Wilde Follow Up Of Celiac Disease Symptoms resolve in 1-3 months Serology level fall substantially in 6 months Biopsies improve more slowly in adults than children Re-biopsy in 1 year Dietitian follow up for compliance MD interest is crucial October

26 Dangers of Non- Compliance Increased mortality Holmes et al Corrao et al. Osteoporosis Cellier Lymphoma Holmes et al. Other cancers Green, 2006 Psychological effects hallert Histologic Healing in Adults Author Countr n % Time y healing on GFD Grefte J 1 Holland 22 0% 2 years Bardella Italy % 2 years M 2 Rubio- USA % 2 years Tapia* 66% 5 years Ciacci C 3 Italy % 7 years Tursi A 4 Italy % 2 years Collin P 5 Finland 65 96% 8 years 1 J Clin Pathol 1988; 2 Histopathology 2007; 3 Digestion 2002; 4 Endoscopy 2006; 5 Gastrointest Endosc 2004 * Rubio-Tapia A, et al. Am J Gastro 2010 October

27 Non Responsive Celiac Disease Primary: no initial response to gluten free diet Secondary: relapse following initial response 17% of celiacs at a support group had diarrhea % of a referral center population 2 9.9% of primary patients 35% of referral patients 1 Fine et al. Gastro, Leffler et al. CGH, 2007 Additional Diagnoses dissaccharidase def SIBO eating disorder gluten exposure refractory sprue microscopic colitis IBS Leffler et al. CGH 2007 October

28 Refractory Celiac Disease Very rare condition Symptomatic malabsorption Severe enteropathy Lack of response to a GFD (exclusion diagnosis) 2 types Immune (Type 1): intraepithelial lymphocyte normal Clonal T-cell (Type 2): aberrant intraepithelial lymphocyte But not overt lymphoma! Nutritional Management Protein calorie malnutrition TPN Enteral elemental feeding Micronutrients Iron, folate, B12 Zinc and copper Bone disease Vitamin D and calcium Parenteral antiresorptive agents October

29 Survival According Subtype Prevalence of Celiac Disease and Gluten Free Diet: NHANES Diagnosed CD Gluten Free Diet Celiac Disease GFD without Dx of CD Untreated CD 1.6 million 1.8 million Rubio-Tapia, et al. AJG % of Caucasians October

30 Non-Celiac Gluten Sensitivity The term NCGS relates to one or more of a variety of immunological, morphological or symptomatic manifestations precipitated by the ingestion of gluten in people p in whom CD has been excluded. Ludvigsson JF, Leffler DA, Bai JC, et al. Gut (2012). Gluten Sensitivity as a Clinical Entity Gluten-sensitive diarrhea without celiac disease first described as a clinical entity in Females, chronic diarrhea, increased cellular infiltration of lamina propria 3-month gluten-free diet (GFD) HLA DQ2 associated with celiac disease Chronic Diarrhea patients with HLA-DQ2 expression profit from a gluten-free diet Cooper BT, et al. Gastro, Howell MD, et al. J Exp Med, (Wahnschaffe, Gastroenterology, 2001) October

31 HLA-DQ2 positive IBS patients had markers ( IELS or gliadin siga ) Cohort of 102 IBS patients, 35% (n=36), 100 were HLA DQ2+ All were TTG IgA % of HLA + IBS patients had IEL s 60 58% had + IgA gliadin 40 or TTG in aspirate. ate Pro oportion of patients, % 20 Increased Aspirate Gliadin or TTG IgA Increased IEL HLA DQ2 + HLA DQ2-0 Wahnschaffe U, et al. Gastro, Normalization of GI symptom score and stool frequency achieved with GFD N=41 IBS-D 6-month GFD GI symptoms and stool frequency HLA DQ2 status and IgG TTG/AGA may predict clinical response to a GFD Histology does not predict response TTG IgG, GS marker? Wahnschaffe U, et al. CGH, October

32 Gluten Sensitivity as a clinical entity: Celiac- Lite Genetic susceptibility HLA DQ2/DQ8 Loss of gluten tolerance Celiac disease: Serum TTG Ab + Mucosal atrophy +? precursor Gluten Sensitivity: IEL + Serum TTG Ab - No mucosal atrophy Response to GFD Gluten Sensitivity Celiac Lite Condition of morphological, immunological, or functional disorder that responds to gluten exclusion in the absence of celiac disease. Gluten sensitive diarrhea Immunopathological changes in the SB mucosa Intraepithelial lymphocytes (IEL) IgA deposits intestinal villi Secreted Ab against gliadin HLA predicted Adapted from Verdu EF, et al. AJG, October

33 Gluten Sensitive GI Symptoms Celiac Like Self identified gluten sensitivity Gi Symptoms Challenge study Randomized Double blind placebo controlled Effect not HLA dependent Highly select group Gluten Causes Gastrointestinal Symptoms in Subjects Without Celiac Disease: A Double-Blind Randomized Placebo-Controlled Trial. Biesiekierski JR et al. AJG 2011 Are there other potential mechanism of gluten in symptoms in IBS? October

34 Multiple immune effects of gluten Stress pathways Gluten Receptors pathways α gliadin p31-43 LGQQQPFPPQQPY MIC IL-15 FQQPQQQYPSSQ SQQPYLQLQ QQQQQQQQQQQQILQQILQQ QVLQQSTYQLLQELCCAHLW? HLA-E CXCR3 Tryptic digested gliadin TLR-4? EGFR pmapk HLA-E MyD88 Epithelial activation Upregulation of IL-15 and EGFR Upregulation of stress-induced MHC-Ib HLA-E surface expression and stabilization APC activation Inflammatory cytokines IL-15? IFN α? APC maturation Inflammatory cytokines IFN-α Increased intestinal permeability Altered Permeability and Mucosal Immune gene expression in Non-Celiac Gluten Sensitivity Decreased IP in GS Increased expression of claudin 4 Reduced Fox p3 Increased TLR2 Comparison group Dyspepsia 5 hour urinary excretion of LA/MA LA/MA is affected by transit Transit may be affected HLA Sapone et al, BMC Medicine, 2011 Vazquez-Roque, AJP, in press October

35 Gluten Intolerance/Sensitivity Enteropathy -CD4 anti-gluten T cells - TG2 - epithelial stress - IL-15 - IFN-α - other - activated IE-CTL Dermatitis (Dermatitis herpetiformis) Other (neuropathy) Ataxia - CD4 anti-gluten T cells Tg6 - other?? - anti-tg2 antibodies AGA (immune complexes) IBS - epithelial stress - epithelial IL-15 Genetic background Environmental factors Adapted from Jabri Gluten sensitivity may have a spectrum of effects Epithelial distress Extraintestinal inflammation - Autoimmunity (T1D) - Latent innate response to gluten IBS Gluten-dependent Extraintestinal manifestation Potential CD with and without Extraintestinal manifestation CD with villous atrophy Mucosal inflammation Epithelial Distress Anti-gluten T cell response Anti-gluten T and B cell response Extraintestinal inflammation? Anti-gluten T and B cell response +/or Anti-TG2 antibodies Anti-gluten T and B cell response + Anti-TG2 antibodies + Epithelial distress Adaptive anti Adaptive anti-gluten immunity TG2 activation? October

36 The Spectrum of Altered Responses to Gluten Beyond Celiac Disease Genetic susceptibility Potential Marsh 0-I Latent celiac disease Marsh III-IV Marsh I&II Dermatitis herpetiformis Anemia Infertility Neurological Disease associations Gluten sensitive IBS Marsh I References: Salmi 2006; Paparo 2005; Kurppa 2009; Vande Voort 2009; Walker 2010; Verdu 2009 Glutensensitive Enteropathy -CD4 anti-gluten T cells - TG2 - epithelial stress -IL-15 -IFN-α -other -activated IE-CTL Dermatitis (Dermatitis herpetiformis) - CD4 anti-gluten T cells? -other? - anti-tg2 antibodies? (immune complexes) Other (neuropathy) IBS - epithelial stress - epithelial IL-15 Genetic background Environmental factors October

37 Challenges Clear define each syndrome and cases Prove gluten dependence De-challenge Re-challenge Double blind Placebo controlled Duration? Safety in neurological syndrome Define mechanism(s) Detection/diagnosis Challenge: How Can We Detect NCGS? Most patients have to find themselves despite us! Self treatment is not satisfactory Missed disease October

38 Challenge: Diagnosis Diagnosis: Rule out celiac disease/ other disease Role of antibodies: secreted/ serum/deposits Anti-gliadin specific for NCGI ( need good controls) IBS for GS IBS Ab to luminal l antigens (dietary/microbes) Intestinal permeability* HLA prediction celiac-lite Evidence Frequently Lacking for Non Coeliac Gluten Intolerance Prospective studies Adequate and appropriate controls Gluten sensitive IBS versus IBS Gluten dependence (DB RCT)* De-challenge Challenge Proven Gluten Exclusivity Other parts of wheat Other foods/ dietary factors Confounding problems common in functional disease Carraccio et al. December issue of AJG October

39 Summary Celiac Disease is common ~1% It can present in many ways or remain covert Frequent in the endoscopy suite Detected by serology ( ttg-iga) biopsy Requires a gluten free diet Refractory sprue is a rare but serious issue A lot of people p eat gluten free Non-celiac gluten sensitivity is real but unclear in frequency, etiology Management of NCGS is still gluten avoidance to avoid symptoms October